Leonard S


Full name : Leonard Sherry

First name : Sherry

Mail : Department of Psychiatry, University of Colorado Denver, Mail Stop 8344, P.O. Box 6511, Aurora, CO 80045

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Country : USA

Email : Sherry.Leonard@ucdenver.edu

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References (64)

Title : The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function - Sinkus_2015_Neuropharmacol_96_274
Author(s) : Sinkus ML , Graw S , Freedman R , Ross RG , Lester HA , Leonard S
Ref : Neuropharmacology , 96 :274 , 2015
Abstract : The human alpha7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is ubiquitously expressed in both the central nervous system and in the periphery. CHRNA7 is genetically linked to multiple disorders with cognitive deficits, including schizophrenia, bipolar disorder, ADHD, epilepsy, Alzheimer's disease, and Rett syndrome. The regulation of CHRNA7 is complex; more than a dozen mechanisms are known, one of which is a partial duplication of the parent gene. Exons 5-10 of CHRNA7 on chromosome 15 were duplicated and inserted 1.6 Mb upstream of CHRNA7, interrupting an earlier partial duplication of two other genes. The chimeric CHRFAM7A gene product, dupalpha7, assembles with alpha7 subunits, resulting in a dominant negative regulation of function. The duplication is human specific, occurring neither in primates nor in rodents. The duplicated alpha7 sequence in exons 5-10 of CHRFAM7A is almost identical to CHRNA7, and thus is not completely queried in high throughput genetic studies (GWAS). Further, pre-clinical animal models of the alpha7nAChR utilized in drug development research do not have CHRFAM7A (dupalpha7) and cannot fully model human drug responses. The wide expression of CHRNA7, its multiple functions and modes of regulation present challenges for study of this gene in disease. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.
ESTHER : Sinkus_2015_Neuropharmacol_96_274
PubMedSearch : Sinkus_2015_Neuropharmacol_96_274
PubMedID: 25701707

Title : The duplicated alpha7 subunits assemble and form functional nicotinic receptors with the full-length alpha7 - Wang_2014_J.Biol.Chem_289_26451
Author(s) : Wang Y , Xiao C , Indersmitten T , Freedman R , Leonard S , Lester HA
Ref : Journal of Biological Chemistry , 289 :26451 , 2014
Abstract : The alpha7 nicotinic acetylcholine receptor gene (CHRNA7) is linked to schizophrenia. A partial duplication of CHRNA7 (CHRFAM7A) is found in humans on 15q13-14. Exon 6 of CHRFAM7A harbors a 2-bp deletion polymorphism, CHRFAM7ADelta2bp, which is also associated with schizophrenia. To understand the effects of the duplicated subunits on alpha7 receptors, we fused alpha7, dupalpha7, and dupDeltaalpha7 subunits with various fluorescent proteins. The duplicated subunits co-localized with full-length alpha7 subunits in mouse neuroblastoma cells (Neuro2a) as well as rat hippocampal neurons. We investigated the interaction between the duplicated subunits and full-length alpha7 by measuring Forster resonance energy transfer using donor recovery after photobleaching and fluorescence lifetime imaging microscopy. The results revealed that the duplicated proteins co-assemble with alpha7. In electrophysiological studies, Leu at the 9'-position in the M2 membrane-spanning segment was replaced with Cys in dupalpha7 or dupDeltaalpha7, and constructs were co-transfected with full-length alpha7 in Neuro2a cells. Exposure to ethylammonium methanethiosulfonate inhibited acetylcholine-induced currents, showing that the assembled functional nicotinic acetylcholine receptors (nAChRs) included the duplicated subunit. Incorporation of dupalpha7 and dupDeltaalpha7 subunits modestly changes the sensitivity of receptors to choline and varenicline. Thus, the duplicated proteins are assembled and transported to the cell membrane together with full-length alpha7 subunits and alter the function of the nAChRs. The characterization of dupalpha7 and dupDeltaalpha7 as well as their influence on alpha7 nAChRs may help explain the pathophysiology of schizophrenia and may suggest therapeutic strategies.
ESTHER : Wang_2014_J.Biol.Chem_289_26451
PubMedSearch : Wang_2014_J.Biol.Chem_289_26451
PubMedID: 25056953

Title : The effects of prenatal stress on alpha4 beta2 and alpha7 hippocampal nicotinic acetylcholine receptor levels in adult offspring - Schulz_2013_Dev.Neurobiol_73_806
Author(s) : Schulz KM , Andrud KM , Burke MB , Pearson JN , Kreisler AD , Stevens KE , Leonard S , Adams CE
Ref : Dev Neurobiol , 73 :806 , 2013
Abstract : Prenatal stress in humans is associated with psychiatric problems in offspring such as anxiety, depression, and schizophrenia. These same illnesses are also associated with neuronal nicotinic acetylcholine receptor (nAChR) dysfunction. Despite the known associations between prenatal stress exposure and offspring mental illness, and between mental illness and nAChR dysfunction, it is not known whether prenatal stress exposure impacts neuronal nAChRs. Thus, we tested the hypothesis that maternal stress alters the development of hippocampal alpha4 beta2 (alpha4beta2 *) and alpha7 (alpha7 *) nicotinic receptor levels in adult offspring. Female Sprague-Dawley rats experienced unpredictable variable stressors two to three times daily during the last week of gestation. At weaning (21 days) the offspring of prenatally stressed (PS) and nonstressed (NS) dams were assigned to same-sex PS or NS groups. In young adulthood (56 days), the brains of offspring were collected and adjacent sections processed for quantitative autoradiography using [125I]-epibatidine (alpha4beta2* nicotinic receptor-selective) and [125I]-alpha-bungarotoxin (alpha-BTX; alpha7* nicotinic receptor-selective) ligands. We found that PS significantly increased hippocampal alpha4beta2* nAChRs of males and females in all subfields analyzed. In contrast, only females showed a trend toward PS-induced increases in alpha7* nAChRs in the dentate gyrus. Interestingly, NS females displayed a significant left-biased lateralization of alpha7* nAChRs in the laconosum moleculare of area CA1, whereas PS females did not, suggesting that PS interfered with normal lateralization patterns of alpha7* nAChRs during development. Taken together, our results suggest that PS impacts the development of hippocampal nAChRs, which may be an important link between PS exposure and risk for neuropsychiatric illness.
ESTHER : Schulz_2013_Dev.Neurobiol_73_806
PubMedSearch : Schulz_2013_Dev.Neurobiol_73_806
PubMedID: 23749479

Title : Perinatal choline effects on neonatal pathophysiology related to later schizophrenia risk - Ross_2013_Am.J.Psychiatry_170_290
Author(s) : Ross RG , Hunter SK , McCarthy L , Beuler J , Hutchison AK , Wagner BD , Leonard S , Stevens KE , Freedman R
Ref : Am J Psychiatry , 170 :290 , 2013
Abstract : OBJECTIVE: Deficient cerebral inhibition is a pathophysiological brain deficit related to poor sensory gating and attention in schizophrenia and other disorders. Cerebral inhibition develops perinatally, influenced by genetic and in utero factors. Amniotic choline activates fetal alpha7-nicotinic acetylcholine receptors and facilitates development of cerebral inhibition. Increasing this activation may protect infants from future illness by promoting normal brain development. The authors investigated the effects of perinatal choline supplementation on the development of cerebral inhibition in human infants. METHOD: A randomized placebo-controlled clinical trial of dietary phosphatidylcholine supplementation was conducted with 100 healthy pregnant women, starting in the second trimester. Supplementation to twice normal dietary levels for mother or newborn continued through the third postnatal month. All women received dietary advice regardless of treatment. Infants' electrophysiological recordings of inhibition of the P50 component of the cerebral evoked response to paired sounds were analyzed. The criterion for inhibition was suppression of the amplitude of the second P50 response by at least half, compared with the first response.
RESULTS: No adverse effects of choline were observed in maternal health and delivery, birth, or infant development. At the fifth postnatal week, the P50 response was suppressed in more choline-treated infants (76%) compared with placebo-treated infants (43%) (effect size=0.7). There was no difference at the 13th week. A CHRNA7 genotype associated with schizophrenia was correlated with diminished P50 inhibition in the placebo-treated infants, but not in the choline-treated infants.
CONCLUSIONS: Neonatal developmental delay in inhibition is associated with attentional problems as the child matures. Perinatal choline activates timely development of cerebral inhibition, even in the presence of gene mutations that otherwise delay it.
ESTHER : Ross_2013_Am.J.Psychiatry_170_290
PubMedSearch : Ross_2013_Am.J.Psychiatry_170_290
PubMedID: 23318559

Title : Promoter methylation and tissue-specific transcription of the alpha7 nicotinic receptor gene, CHRNA7 - Canastar_2012_J.Mol.Neurosci_47_389
Author(s) : Canastar A , Logel J , Graw S , Finlay-Schultz J , Osborne C , Palionyte M , Drebing C , Plehaty M , Wilson L , Eyeson R , Leonard S
Ref : Journal of Molecular Neuroscience , 47 :389 , 2012
Abstract : The alpha7 nicotinic acetylcholine receptor is known to regulate a wide variety of developmental and secretory functions in neural and non-neural tissues. The mechanisms that regulate its transcription in these varied tissues are not well understood. Epigenetic processes may play a role in the tissue-specific regulation of mRNA expression from the alpha7 nicotinic receptor subunit gene, CHRNA7. Promoter methylation was correlated with CHRNA7 mRNA expression in various tissue types and the role of DNA methylation in regulating transcription from the gene was tested by using DNA methyltransferase (DNMT1) inhibitors and methyl donors. CHRNA7 mRNA expression was silenced in SH-EP1 cells and bisulfite sequencing PCR revealed the CHRNA7 proximal promoter was hypermethylated. The proximal promoter was hypomethylated in the cell lines HeLa, SH-SY5Y, and SK-N-BE which express varying levels of CHRNA7 mRNA. Expression of CHRNA7 mRNA was present in SH-EP1 cells after treatment with the methylation inhibitor, 5-aza-2-deoxycytidine (5-Aza-CdR), and increased in SH-EP1 and HeLa cells using another methylation inhibitor, zebularine (ZEB). Transcription from the CHRNA7 promoter in HeLa cells was increased when the methyl donor methionine (MET) was absent from the media. Using methylation-sensitive restriction enzyme analysis (MSRE), there was a strong inverse correlation between CHRNA7 mRNA levels and promoter DNA methylation across several human tissue types. The results support a role for DNA methylation of the proximal promoter in regulation of CHRNA7 transcription.
ESTHER : Canastar_2012_J.Mol.Neurosci_47_389
PubMedSearch : Canastar_2012_J.Mol.Neurosci_47_389
PubMedID: 22052086

Title : Multiple genes in the 15q13-q14 chromosomal region are associated with schizophrenia - Stephens_2012_Psychiatr.Genet_22_1
Author(s) : Stephens SH , Franks A , Berger R , Palionyte M , Fingerlin TE , Wagner B , Logel J , Olincy A , Ross RG , Freedman R , Leonard S
Ref : Psychiatr Genet , 22 :1 , 2012
Abstract : OBJECTIVE: The chromosomal region, 15q13-q14, including the alpha7 nicotinic acetylcholine receptor gene, CHRNA7, is a replicated region for schizophrenia. This study fine-mapped genes at 15q13-q14 to determine whether the association is unique to CHRNA7.
METHODS: Family-based and case-control association studies were performed on Caucasian-non-Hispanic and African-American individuals from 120 families as well as 468 individual patients with schizophrenia and 144 well-characterized controls. Single-nucleotide polymorphism (SNP) markers were genotyped, and association analyses carried out for the outcomes of schizophrenia, smoking, and smoking in schizophrenia.
RESULTS: Three genes were associated with schizophrenia in both ethnic populations: TRPM1, KLF13, and RYR3. Two SNPs in CHRNA7 were associated with schizophrenia in African-Americans, and a second SNP in CHRNA7 was significant for an association with smoking and smoking in schizophrenia in Caucasians. CONCLUSION: Results of these studies support association of the 15q13-q14 region with schizophrenia. The broad positive association suggests that more than one 15q gene may be contributing to the disorder, either in combination or through a regulatory mechanism.
ESTHER : Stephens_2012_Psychiatr.Genet_22_1
PubMedSearch : Stephens_2012_Psychiatr.Genet_22_1
PubMedID: 21970977

Title : Effects of an alpha 7-nicotinic agonist on default network activity in schizophrenia - Tregellas_2011_Biol.Psychiatry_69_7
Author(s) : Tregellas JR , Tanabe J , Rojas DC , Shatti S , Olincy A , Johnson L , Martin LF , Soti F , Kem WR , Leonard S , Freedman R
Ref : Biological Psychiatry , 69 :7 , 2011
Abstract : BACKGROUND: 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB-A) is a partial agonist at alpha7 nicotinic acetylcholine receptors that has been evaluated clinically for treatment of schizophrenia. This study examined the effects of DMXB-A on default network activity as a biomarker for drug effects on pathologic brain function associated with schizophrenia.
METHODS: Placebo and two doses of DMXB-A were administered in a random, double-blind crossover design during a Phase 2 study of DMXB-A. Functional magnetic resonance imaging was performed on 16 nonsmoking patients with schizophrenia while they performed a simple eye movement task. Independent component analysis was used to identify the default network component. Default network changes were evaluated in the context of a polymorphism in CHRNA7, the alpha7-nicotinic acetylcholine receptor subunit gene, which was previously found to be associated with schizophrenia.
RESULTS: Compared with placebo, both 150 and 75 mg twice daily DMXB-A altered default network activity, including a reduction in posterior cingulate, inferior parietal cortex, and medial frontal gyrus activity and an increase in precuneus activity. The most robust difference, posterior cingulate activity reduction, was affected by CHRNA7 genotype.
CONCLUSIONS: The observed DMXB-A-related changes are consistent with improved default network function in schizophrenia. Pharmacogenetic analysis indicates mediation of the effect through the alpha7-nicotinic receptor. These results further implicate nicotinic cholinergic dysfunction in the disease and suggest that default network activity may be a useful indicator of biological effects of novel therapeutic agents.
ESTHER : Tregellas_2011_Biol.Psychiatry_69_7
PubMedSearch : Tregellas_2011_Biol.Psychiatry_69_7
PubMedID: 20728875

Title : Poster: LTD deficit in alpha7 neuronal nicotinic receptor (alpha7*) knockout mice is strain dependent -
Author(s) : Freund RK , Graw SL , Floyd K , Leonard S , DellAcqua ML
Ref : Biochemical Pharmacology , 82 :1037 , 2011

Title : Poster: Hippocampal Class I Major Histocompatibility Complex genes are differentially expressed in schizophrenic smokers -
Author(s) : Sinkus ML , Mexal S , Berger R , Leonard S
Ref : Biochemical Pharmacology , 82 :1046 , 2011

Title : Transcriptional repression of the alpha7 nicotinic acetylcholine receptor subunit gene (CHRNA7) by activating protein-2alpha (AP-2alpha) - Finlay-Schultz_2011_J.Biol.Chem_286_42123
Author(s) : Finlay-Schultz J , Canastar A , Short M , El Gazzar M , Coughlan C , Leonard S
Ref : Journal of Biological Chemistry , 286 :42123 , 2011
Abstract : The CHRNA7 gene, which encodes the alpha7 nicotinic acetylcholine receptor (alpha7*nAChR), has been implicated as a candidate gene in schizophrenia. Expression of the alpha7*nAChR mRNA and protein are reduced in multiple regions of post-mortem brain from patients diagnosed with schizophrenia. Transcriptional regulation may therefore be an important mechanism for the regulation of this gene. A 230-bp proximal promoter fragment, necessary for transcription in cultured neuroblastoma cells, was used to study a putative AP-2alpha binding site. Mutation of the site indicates that AP-2alpha plays a negative role in regulating CHRNA7 transcription. This was confirmed through knockdown and overexpression of AP-2alpha. Electrophoretic mobility shift assays (EMSAs) identified positive DNA-protein interaction at this same site, and supershift assays indicate that the complex includes AP-2alpha. The interaction was confirmed in cells using chromatin immunoprecipitation (ChIP). DNA methylation was discovered as an anomalous mechanism for CHRNA7 regulation in one cell line. These studies suggest a role for AP-2alpha regulation of CHRNA7 mRNA expression in multiple tissues during development.
ESTHER : Finlay-Schultz_2011_J.Biol.Chem_286_42123
PubMedSearch : Finlay-Schultz_2011_J.Biol.Chem_286_42123
PubMedID: 21979958

Title : The alpha7 nicotinic acetylcholine receptor and the acute stress response: maternal genotype determines offspring phenotype - Sinkus_2011_Physiol.Behav_104_321
Author(s) : Sinkus ML , Wamboldt MZ , Barton A , Fingerlin TE , Laudenslager ML , Leonard S
Ref : Physiol Behav , 104 :321 , 2011
Abstract : alpha7 Nicotinic acetylcholine receptors (alpha7nAchRs) modulate immune activation by suppressing production of pro-inflammatory cytokines in peripheral immune cells. alpha7nAchRs also modulate inhibitory output in the hippocampus, which provides input to key circuits of the HPA axis. Therefore, the alpha7 nicotinic acetylcholine receptor gene (CHRNA7) may be associated with cortisol stress response. Polymorphisms in the CHRNA7 promoter decrease its expression and may dampen the cholinergic response, leading to an increase in inflammation. Increased inflammation may change the intrauterine environment, altering neuroendocrine development in the offspring. Maternal CHRNA7 genotype could affect an offspring's HPA regulation via reprogramming in utero. Patients with allergic disorders have a differential cortisol response to stress. This study utilized samples collected from a cohort of 198 adolescents in a previous study of atopic disorders, who demonstrated a disturbance in HPA response associated with atopy. Salivary cortisol samples collected from the adolescents after a series of laboratory procedures and DNA samples collected from the adolescents and their parents were used for further analysis. DNA samples were genotyped for allelic variation in the CHRNA7 promoter. Genetic association analyses with the cortisol levels were performed in the adolescents. Maternal genotype influences were investigated for the CHRNA7 gene. We also included maternal and child atopy diagnosis as covariates in determining cortisol levels and tested for association of CHRNA7 to atopy. Polymorphisms in the CHRNA7 promoter were associated with lower cortisol levels after a small laboratory stress. Our findings also show that although the child's CHRNA7 genotype affects stress response, the maternal genotype has a stronger influence on cortisol release after stress in male offspring. These effects were independent of atopy status.
ESTHER : Sinkus_2011_Physiol.Behav_104_321
PubMedSearch : Sinkus_2011_Physiol.Behav_104_321
PubMedID: 21073885

Title : The chimeric gene CHRFAM7A, a partial duplication of the CHRNA7 gene, is a dominant negative regulator of alpha7*nAChR function - Araud_2011_Biochem.Pharmacol_82(8)_904
Author(s) : Araud T , Graw S , Berger R , Lee M , Neveu E , Bertrand D , Leonard S
Ref : Biochemical Pharmacology , 82 :904 , 2011
Abstract : The human alpha7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is a candidate gene for schizophrenia and an important drug target for cognitive deficits in the disorder. Activation of the alpha7*nAChR, results in opening of the channel and entry of mono- and divalent cations, including Ca(2+), that presynaptically participates to neurotransmitter release and postsynaptically to down-stream changes in gene expression. Schizophrenic patients have low levels of alpha7*nAChR, as measured by binding of the ligand [(125)I]-alpha-bungarotoxin (I-BTX). The structure of the gene, CHRNA7, is complex. During evolution, CHRNA7 was partially duplicated as a chimeric gene (CHRFAM7A), which is expressed in the human brain and elsewhere in the body. The association between a 2bp deletion in CHRFAM7A and schizophrenia suggested that this duplicate gene might contribute to cognitive impairment. To examine the putative contribution of CHRFAM7A on receptor function, co-expression of alpha7 and the duplicate genes was carried out in cell lines and Xenopus oocytes. Expression of the duplicate alone yielded protein expression but no functional receptor and co-expression with alpha7 caused a significant reduction of the amplitude of the ACh-evoked currents. Reduced current amplitude was not correlated with a reduction of I-BTX binding, suggesting the presence of non-functional (ACh-silent) receptors. This hypothesis is supported by a larger increase of the ACh-evoked current by the allosteric modulator 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596) in cells expressing the duplicate than in the control. These results suggest that CHRFAM7A acts as a dominant negative modulator of CHRNA7 function and is critical for receptor regulation in humans.
ESTHER : Araud_2011_Biochem.Pharmacol_82(8)_904
PubMedSearch : Araud_2011_Biochem.Pharmacol_82(8)_904
PubMedID: 21718690

Title : Differential regulation of alpha7 nicotinic receptor gene (CHRNA7) expression in schizophrenic smokers - Mexal_2010_J.Mol.Neurosci_40_185
Author(s) : Mexal S , Berger R , Logel J , Ross RG , Freedman R , Leonard S
Ref : Journal of Molecular Neuroscience , 40 :185 , 2010
Abstract : The alpha7 neuronal nicotinic receptor gene (CHRNA7) has been implicated in the pathophysiology of schizophrenia by genetic and pharmacological studies. Expression of the alpha7* receptor, as measured by [(125)I]alpha-bungarotoxin autoradiography, is decreased in postmortem brain of schizophrenic subjects compared to non-mentally ill controls. Most schizophrenic patients are heavy smokers, with high levels of serum cotinine. Smoking changes the expression of multiple genes and differentially regulates gene expression in schizophrenic hippocampus. We examined the effects of smoking on CHRNA7 expression in the same tissue and find that smoking differentially regulates expression of both mRNA and protein for this gene. CHRNA7 mRNA and protein levels are significantly lower in schizophrenic nonsmokers compared to control nonsmokers and are brought to control levels in schizophrenic smokers. Sufficient protein but low surface expression of the alpha7* receptor, seen in the autoradiographic studies, suggests aberrant assembly or trafficking of the receptor.
ESTHER : Mexal_2010_J.Mol.Neurosci_40_185
PubMedSearch : Mexal_2010_J.Mol.Neurosci_40_185
PubMedID: 19680823

Title : Research review: Cholinergic mechanisms, early brain development, and risk for schizophrenia - Ross_2010_J.Child.Psychol.Psychiatry_51_535
Author(s) : Ross RG , Stevens KE , Proctor WR , Leonard S , Kisley MA , Hunter SK , Freedman R , Adams CE
Ref : J Child Psychol Psychiatry , 51 :535 , 2010
Abstract : The onset of diagnostic symptomology for neuropsychiatric diseases is often the end result of a decades-long process of aberrant brain development. Identification of novel treatment strategies aimed at normalizing early brain development and preventing mental illness should be a major therapeutic goal. However, there are few models for how this goal might be achieved. This review uses the development of a psychophysiological correlate of attentional deficits in schizophrenia to propose a developmental model with translational primary prevention implications. Review of genetic and neurobiological studies suggests that an early interaction between alpha7 nicotinic receptor density and choline availability may contribute to the development of schizophrenia-associated attentional deficits. Therapeutic implications, including perinatal dietary choline supplementation, are discussed.
ESTHER : Ross_2010_J.Child.Psychol.Psychiatry_51_535
PubMedSearch : Ross_2010_J.Child.Psychol.Psychiatry_51_535
PubMedID: 19925602

Title : The B73 maize genome: complexity, diversity, and dynamics - Schnable_2009_Science_326_1112
Author(s) : Schnable PS , Ware D , Fulton RS , Stein JC , Wei F , Pasternak S , Liang C , Zhang J , Fulton L , Graves TA , Minx P , Reily AD , Courtney L , Kruchowski SS , Tomlinson C , Strong C , Delehaunty K , Fronick C , Courtney B , Rock SM , Belter E , Du F , Kim K , Abbott RM , Cotton M , Levy A , Marchetto P , Ochoa K , Jackson SM , Gillam B , Chen W , Yan L , Higginbotham J , Cardenas M , Waligorski J , Applebaum E , Phelps L , Falcone J , Kanchi K , Thane T , Scimone A , Thane N , Henke J , Wang T , Ruppert J , Shah N , Rotter K , Hodges J , Ingenthron E , Cordes M , Kohlberg S , Sgro J , Delgado B , Mead K , Chinwalla A , Leonard S , Crouse K , Collura K , Kudrna D , Currie J , He R , Angelova A , Rajasekar S , Mueller T , Lomeli R , Scara G , Ko A , Delaney K , Wissotski M , Lopez G , Campos D , Braidotti M , Ashley E , Golser W , Kim H , Lee S , Lin J , Dujmic Z , Kim W , Talag J , Zuccolo A , Fan C , Sebastian A , Kramer M , Spiegel L , Nascimento L , Zutavern T , Miller B , Ambroise C , Muller S , Spooner W , Narechania A , Ren L , Wei S , Kumari S , Faga B , Levy MJ , McMahan L , Van Buren P , Vaughn MW , Ying K , Yeh CT , Emrich SJ , Jia Y , Kalyanaraman A , Hsia AP , Barbazuk WB , Baucom RS , Brutnell TP , Carpita NC , Chaparro C , Chia JM , Deragon JM , Estill JC , Fu Y , Jeddeloh JA , Han Y , Lee H , Li P , Lisch DR , Liu S , Liu Z , Nagel DH , McCann MC , SanMiguel P , Myers AM , Nettleton D , Nguyen J , Penning BW , Ponnala L , Schneider KL , Schwartz DC , Sharma A , Soderlund C , Springer NM , Sun Q , Wang H , Waterman M , Westerman R , Wolfgruber TK , Yang L , Yu Y , Zhang L , Zhou S , Zhu Q , Bennetzen JL , Dawe RK , Jiang J , Jiang N , Presting GG , Wessler SR , Aluru S , Martienssen RA , Clifton SW , McCombie WR , Wing RA , Wilson RK
Ref : Science , 326 :1112 , 2009
Abstract : We report an improved draft nucleotide sequence of the 2.3-gigabase genome of maize, an important crop plant and model for biological research. Over 32,000 genes were predicted, of which 99.8% were placed on reference chromosomes. Nearly 85% of the genome is composed of hundreds of families of transposable elements, dispersed nonuniformly across the genome. These were responsible for the capture and amplification of numerous gene fragments and affect the composition, sizes, and positions of centromeres. We also report on the correlation of methylation-poor regions with Mu transposon insertions and recombination, and copy number variants with insertions and/or deletions, as well as how uneven gene losses between duplicated regions were involved in returning an ancient allotetraploid to a genetically diploid state. These analyses inform and set the stage for further investigations to improve our understanding of the domestication and agricultural improvements of maize.
ESTHER : Schnable_2009_Science_326_1112
PubMedSearch : Schnable_2009_Science_326_1112
PubMedID: 19965430
Gene_locus related to this paper: maize-b4ffc7 , maize-b6u7e1 , maize-c0pcy5 , maize-c0pgf7 , maize-c0pgw1 , maize-c0pfl3 , maize-b4fpr7 , maize-k7vy73 , maize-a0a096swr3 , maize-k7v3i9 , maize-b6u9v9 , maize-a0a3l6e780 , maize-b4fv80 , maize-a0a1d6nse2 , maize-c4j9a1 , maize-k7uba1

Title : A 2-base pair deletion polymorphism in the partial duplication of the alpha7 nicotinic acetylcholine gene (CHRFAM7A) on chromosome 15q14 is associated with schizophrenia - Sinkus_2009_Brain.Res_1291_1
Author(s) : Sinkus ML , Lee MJ , Gault J , Logel J , Short M , Freedman R , Christian SL , Lyon J , Leonard S
Ref : Brain Research , 1291 :1 , 2009
Abstract : Multiple genetic linkage studies support the hypothesis that the 15q13-14 chromosomal region contributes to the etiology of schizophrenia. Among the putative candidate genes in this area are the alpha7 nicotinic acetylcholine receptor gene (CHRNA7) and its partial duplication, CHRFAM7A. A large chromosomal segment including the CHRFAM7A gene locus, but not the CHRNA7 locus, is deleted in some individuals. The CHRFAM7A gene contains a polymorphism consisting of a 2 base pair (2 bp) deletion at position 497-498 bp of exon 6. We employed PCR-based methods to quantify the copy number of CHRFAM7A and the presence of the 2 bp polymorphism in a large, multi-ethnic population. The 2 bp polymorphism was associated with schizophrenia in African Americans (genotype p=0.005, allele p=0.015), and in Caucasians (genotype p=0.015, allele p=0.009). We conclude that the presence of the 2 bp polymorphism at the CHRFAM7A locus may have a functional significance in schizophrenia.
ESTHER : Sinkus_2009_Brain.Res_1291_1
PubMedSearch : Sinkus_2009_Brain.Res_1291_1
PubMedID: 19631623

Title : Association of the 5'-upstream regulatory region of the alpha7 nicotinic acetylcholine receptor subunit gene (CHRNA7) with schizophrenia - Stephens_2009_Schizophr.Res_109_102
Author(s) : Stephens SH , Logel J , Barton A , Franks A , Schultz J , Short M , Dickenson J , James B , Fingerlin TE , Wagner B , Hodgkinson C , Graw S , Ross RG , Freedman R , Leonard S
Ref : Schizophr Res , 109 :102 , 2009
Abstract : BACKGROUND: The alpha7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) is localized in a chromosomal region (15q14) linked to schizophrenia in multiple independent studies. CHRNA7 was selected as the best candidate gene in the region for a well-documented endophenotype of schizophrenia, the P50 sensory processing deficit, by genetic linkage and biochemical studies.
METHODS: Subjects included Caucasian-Non Hispanic and African-American case-control subjects collected in Denver, and schizophrenic subjects from families in the NIMH Genetics Initiative on Schizophrenia. Thirty-five single nucleotide polymorphisms (SNPs) in the 5'-upstream regulatory region of CHRNA7 were genotyped for association with schizophrenia, and for smoking in schizophrenia.
RESULTS: The rs3087454 SNP, located at position -1831 bp in the upstream regulatory region of CHRNA7, was significantly associated with schizophrenia in the case-control samples after multiple-testing correction (P=0.0009, African American; P=0.013, Caucasian-Non Hispanic); the association was supported in family members. There was nominal association of this SNP with smoking in schizophrenia.
CONCLUSIONS: The data support association of regulatory region polymorphisms in the CHRNA7 gene with schizophrenia.
ESTHER : Stephens_2009_Schizophr.Res_109_102
PubMedSearch : Stephens_2009_Schizophr.Res_109_102
PubMedID: 19181484

Title : Poster: Role of Sp1 and AP-2 in the transcriptional regulation of the CHRNA7 gene and the link to schizophrenia -
Author(s) : Schultz JF , Short M , Graw S , Leonard S
Ref : Biochemical Pharmacology , 78 :910 , 2009

Title : Smoking, Genetics and Schizophrenia: Evidence for Self Medication - Leonard_2007_J.Dual.Diagn_3_43
Author(s) : Leonard S , Mexal S , Freedman R
Ref : J Dual Diagn , 3 :43 , 2007
Abstract : Schizophrenia is a common mental illness with a high prevalence of smoking. More than 80% of schizophrenics smoke compared to 25% of the general population. Both schizophrenia and tobacco use have strong genetic components, which may overlap. It has been suggested that smoking in schizophrenia may be a form of self-medication in an attempt to treat an underlying biological pathology. Smoking normalizes auditory evoked potential and eye tracking deficits in schizophrenia, as well as improving cognitive function. Nicotine acts through a family of nicotinic receptors with either high or low affinity for nicotine. The loci for several of these receptors have been genetically linked to both smoking and to schizophrenia. Smoking changes gene expression for more than 200 genes in human hippocampus, and differentially normalizes aberrant gene expression in schizophrenia. The alpha7* nicotinic receptor, linked to schizophrenia and smoking, has been implicated in sensory processing deficits and is important for cognition and protection from neurotoxicity. Nicotine, however, has multiple health risks and desensitizes the receptor. A Phase I trial of DMXB-A, an alpha7* agonist, shows improvement in both P50 gating and in cognition, suggesting that further development of nicotinic cholinergic drugs is a promising direction in schizophrenia research.
ESTHER : Leonard_2007_J.Dual.Diagn_3_43
PubMedSearch : Leonard_2007_J.Dual.Diagn_3_43
PubMedID: 19122786

Title : Sensory gating and alpha-7 nicotinic receptor gene allelic variants in schizoaffective disorder, bipolar type - Martin_2007_Am.J.Med.Genet.B.Neuropsychiatr.Genet_144B_611
Author(s) : Martin LF , Leonard S , Hall MH , Tregellas JR , Freedman R , Olincy A
Ref : American Journal of Medicine Genet B Neuropsychiatr Genet , 144B :611 , 2007
Abstract : OBJECTIVES: Single nucleotide allelic variants in the promoter region of the chromosome 15 alpha-7 acetylcholine nicotinic receptor gene (CHRNA7) are associated with both schizophrenia and the P50 auditory evoked potential sensory gating deficit. The purpose of this study was to determine if CHRNA7 promoter allelic variants are also associated with abnormal P50 ratios in persons with schizoaffective disorder, bipolar type.
METHODS: P50 auditory evoked potentials were recorded in a paired stimulus paradigm in 17 subjects with schizoaffective disorder, bipolar type. The P50 test to conditioning ratio was used as the measure of sensory gating. Mutation screening of the CHRNA7 promoter region was performed on the subjects' DNA samples. Comparisons to previously obtained data from persons with schizophrenia and controls were made.
RESULTS: Subjects with schizophrenia, regardless of allele status, had an abnormal mean P50 ratio. Subjects with schizoaffective disorder, bipolar type and a variant allele had an abnormal mean P50 ratio, whereas those schizoaffective subjects with the common alleles had a normal mean P50 ratio. Normal control subjects had a normal mean ratio, but controls with variant alleles had higher P50 ratios.
CONCLUSIONS: In persons with bipolar type schizoaffective disorder, CHRNA7 promoter region allelic variants are linked to the capacity to inhibit the P50 auditory evoked potential and thus are associated with a type of illness genetically and biologically more similar to schizophrenia.
ESTHER : Martin_2007_Am.J.Med.Genet.B.Neuropsychiatr.Genet_144B_611
PubMedSearch : Martin_2007_Am.J.Med.Genet.B.Neuropsychiatr.Genet_144B_611
PubMedID: 17192894

Title : Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia - Olincy_2006_Arch.Gen.Psychiatry_63_630
Author(s) : Olincy A , Harris JG , Johnson LL , Pender V , Kongs S , Allensworth D , Ellis J , Zerbe GO , Leonard S , Stevens KE , Stevens JO , Martin L , Adler LE , Soti F , Kem WR , Freedman R
Ref : Arch Gen Psychiatry , 63 :630 , 2006
Abstract : CONTEXT: The alpha7 nicotinic acetylcholine receptor gene, CHRNA7, is associated with genetic transmission of schizophrenia and related cognitive and neurophysiological sensory gating deficits. Cognitive dysfunction is responsible for significant psychosocial disability in schizophrenia. Nicotine, a low-potency agonist at the alpha7 receptor, has some positive effects on neurophysiological and neurocognitive deficits associated with schizophrenia, which suggests that more effective receptor activation might meaningfully enhance cognition in schizophrenia. OBJECTIVES: To determine if 3-[(2,4-dimethoxy)benzylidene]anabaseine (DMXB-A), a natural alkaloid derivative and a partial alpha7 nicotinic cholinergic agonist, significantly improves neurocognition, and to assess, by effects on P50 auditory evoked potential inhibition, whether its neurobiological actions are consistent with activation of alpha7 nicotinic receptors. DESIGN: Randomized, double-blind crossover trial of 2 drug doses and 1 placebo. SETTING: General clinical research center. PATIENTS: Twelve persons with schizophrenia who did not smoke and were concurrently treated with antipsychotic drugs. One person was withdrawn because of a transient decrease in white blood cell count. INTERVENTION: Administration of DMXB-A. MAIN OUTCOME MEASURES: Total scale score of the Repeatable Battery for the Assessment of Neuropsychological Status and P50 inhibitory gating.
RESULTS: Significant neurocognitive improvement was found on the Repeatable Battery for the Assessment of Neuropsychological Status total scale score, particularly for the lower DMXB-A dose compared with placebo. Effects were greater than those of nicotine in a similar study. Significant improvement in P50 inhibition also occurred. Patients generally tolerated the drug well.
CONCLUSIONS: An alpha7 nicotinic agonist appears to have positive effects on neurocognition in persons with schizophrenia. Longer trials are needed to determine the clinical utility of this novel treatment strategy.
ESTHER : Olincy_2006_Arch.Gen.Psychiatry_63_630
PubMedSearch : Olincy_2006_Arch.Gen.Psychiatry_63_630
PubMedID: 16754836

Title : Smoking cessation and schizophrenia -
Author(s) : Leonard S , Adams CE
Ref : Am J Psychiatry , 163 :1877 , 2006
PubMedID: 17074936

Title : Characterization of allelic variants at chromosome 15q14 in schizophrenia - Freedman_2006_Genes.Brain.Behav_5 Suppl 1_14
Author(s) : Freedman R , Leonard S , Waldo M , Gault J , Olincy A , Adler LE
Ref : Genes Brain Behav , 5 Suppl 1 :14 , 2006
Abstract : Evidence of genetic linkage for schizophrenia at chromosome 15q14 has been reported in nine independent studies, but the molecular variants responsible for transmission of genetic risk are unknown. National Institute of Mental Health Schizophrenia Genetics Initiative families were genotyped for single nucleotide polymorphisms (SNPs) and dinucleotide repeat markers in the 15q14 linkage region and analyzed based on the presence of particular alleles of the dinucleotide repeat marker D15S165 in the 15q14 region. Two alleles showed both familial transmission disequilibrium and population-wide association with schizophrenia. The two groups identified by these two D15S165 alleles differ in age of onset, number of hospitalizations and intensity of nicotine abuse, as well as in predominant ethnicity. Variations in the frequency of SNPs in CHRNA7, the alpha-7-nicotinic acetylcholine receptor subunit gene at 15q14, were found in each group. Further sequencing in these two groups may yield more definitive identification of the molecular pathology.
ESTHER : Freedman_2006_Genes.Brain.Behav_5 Suppl 1_14
PubMedSearch : Freedman_2006_Genes.Brain.Behav_5 Suppl 1_14
PubMedID: 16417613

Title : Generation and annotation of the DNA sequences of human chromosomes 2 and 4 - Hillier_2005_Nature_434_724
Author(s) : Hillier LW , Graves TA , Fulton RS , Fulton LA , Pepin KH , Minx P , Wagner-McPherson C , Layman D , Wylie K , Sekhon M , Becker MC , Fewell GA , Delehaunty KD , Miner TL , Nash WE , Kremitzki C , Oddy L , Du H , Sun H , Bradshaw-Cordum H , Ali J , Carter J , Cordes M , Harris A , Isak A , Van Brunt A , Nguyen C , Du F , Courtney L , Kalicki J , Ozersky P , Abbott S , Armstrong J , Belter EA , Caruso L , Cedroni M , Cotton M , Davidson T , Desai A , Elliott G , Erb T , Fronick C , Gaige T , Haakenson W , Haglund K , Holmes A , Harkins R , Kim K , Kruchowski SS , Strong CM , Grewal N , Goyea E , Hou S , Levy A , Martinka S , Mead K , McLellan MD , Meyer R , Randall-Maher J , Tomlinson C , Dauphin-Kohlberg S , Kozlowicz-Reilly A , Shah N , Swearengen-Shahid S , Snider J , Strong JT , Thompson J , Yoakum M , Leonard S , Pearman C , Trani L , Radionenko M , Waligorski JE , Wang C , Rock SM , Tin-Wollam AM , Maupin R , Latreille P , Wendl MC , Yang SP , Pohl C , Wallis JW , Spieth J , Bieri TA , Berkowicz N , Nelson JO , Osborne J , Ding L , Sabo A , Shotland Y , Sinha P , Wohldmann PE , Cook LL , Hickenbotham MT , Eldred J , Williams D , Jones TA , She X , Ciccarelli FD , Izaurralde E , Taylor J , Schmutz J , Myers RM , Cox DR , Huang X , McPherson JD , Mardis ER , Clifton SW , Warren WC , Chinwalla AT , Eddy SR , Marra MA , Ovcharenko I , Furey TS , Miller W , Eichler EE , Bork P , Suyama M , Torrents D , Waterston RH , Wilson RK
Ref : Nature , 434 :724 , 2005
Abstract : Human chromosome 2 is unique to the human lineage in being the product of a head-to-head fusion of two intermediate-sized ancestral chromosomes. Chromosome 4 has received attention primarily related to the search for the Huntington's disease gene, but also for genes associated with Wolf-Hirschhorn syndrome, polycystic kidney disease and a form of muscular dystrophy. Here we present approximately 237 million base pairs of sequence for chromosome 2, and 186 million base pairs for chromosome 4, representing more than 99.6% of their euchromatic sequences. Our initial analyses have identified 1,346 protein-coding genes and 1,239 pseudogenes on chromosome 2, and 796 protein-coding genes and 778 pseudogenes on chromosome 4. Extensive analyses confirm the underlying construction of the sequence, and expand our understanding of the structure and evolution of mammalian chromosomes, including gene deserts, segmental duplications and highly variant regions.
ESTHER : Hillier_2005_Nature_434_724
PubMedSearch : Hillier_2005_Nature_434_724
PubMedID: 15815621
Gene_locus related to this paper: human-ABHD1 , human-LDAH , human-ABHD18 , human-KANSL3 , human-PGAP1 , human-PREPL

Title : Early biomarkers of psychosis - Freedman_2005_Dialogues.Clin.Neurosci_7_17
Author(s) : Freedman R , Ross R , Leonard S , Myles-Worsley M , Adams CE , Waldo M , Tregellas J , Martin L , Olincy A , Tanabe J , Kisley MA , Hunter S , Stevens KE
Ref : Dialogues Clin Neurosci , 7 :17 , 2005
Abstract : Biological traits that are predictive of the later development of psychosis have not yet been identified. The complex, multidetermined nature of schizophrenia and other psychoses makes it unlikely that any single biomarker will be both sensitive and specific enough to unambiguously identify individuals who will later become psychotic. However, current genetic research has begun to identify genes associated with schizophrenia, some of which have phenotypes that appear early in life. While these phenotypes have low predictive power for identifying individuals who will become psychotic, they do serve as biomarkers for pathophysiological processes that can become the targets of prevention strategies. Examples are given from work on the role of the alpha(T)nicotinic receptor and its gene CHRNA7 on chromosome 15 in the neurobiology and genetic transmission of schizophrenia.
ESTHER : Freedman_2005_Dialogues.Clin.Neurosci_7_17
PubMedSearch : Freedman_2005_Dialogues.Clin.Neurosci_7_17
PubMedID: 16060593

Title : Comparison of genome degradation in Paratyphi A and Typhi, human-restricted serovars of Salmonella enterica that cause typhoid - McClelland_2004_Nat.Genet_36_1268
Author(s) : McClelland M , Sanderson KE , Clifton SW , Latreille P , Porwollik S , Sabo A , Meyer R , Bieri T , Ozersky P , McLellan M , Harkins CR , Wang C , Nguyen C , Berghoff A , Elliott G , Kohlberg S , Strong C , Du F , Carter J , Kremizki C , Layman D , Leonard S , Sun H , Fulton L , Nash W , Miner T , Minx P , Delehaunty K , Fronick C , Magrini V , Nhan M , Warren W , Florea L , Spieth J , Wilson RK
Ref : Nat Genet , 36 :1268 , 2004
Abstract : Salmonella enterica serovars often have a broad host range, and some cause both gastrointestinal and systemic disease. But the serovars Paratyphi A and Typhi are restricted to humans and cause only systemic disease. It has been estimated that Typhi arose in the last few thousand years. The sequence and microarray analysis of the Paratyphi A genome indicates that it is similar to the Typhi genome but suggests that it has a more recent evolutionary origin. Both genomes have independently accumulated many pseudogenes among their approximately 4,400 protein coding sequences: 173 in Paratyphi A and approximately 210 in Typhi. The recent convergence of these two similar genomes on a similar phenotype is subtly reflected in their genotypes: only 30 genes are degraded in both serovars. Nevertheless, these 30 genes include three known to be important in gastroenteritis, which does not occur in these serovars, and four for Salmonella-translocated effectors, which are normally secreted into host cells to subvert host functions. Loss of function also occurs by mutation in different genes in the same pathway (e.g., in chemotaxis and in the production of fimbriae).
ESTHER : McClelland_2004_Nat.Genet_36_1268
PubMedSearch : McClelland_2004_Nat.Genet_36_1268
PubMedID: 15531882
Gene_locus related to this paper: salen-OPDB , salty-AES , salty-BIOH , salty-DLHH , salty-ENTF , salty-FES , salty-IROD , salty-IROE , salty-P74847 , salty-PLDB , salty-STM2547 , salty-STM4506 , salty-STY1441 , salty-STY2428 , salty-STY3846 , salty-yafa , salty-YBFF , salty-ycfp , salty-YFBB , salty-YHET , salty-YQIA

Title : The DNA sequence of human chromosome 7 - Hillier_2003_Nature_424_157
Author(s) : Hillier LW , Fulton RS , Fulton LA , Graves TA , Pepin KH , Wagner-McPherson C , Layman D , Maas J , Jaeger S , Walker R , Wylie K , Sekhon M , Becker MC , O'Laughlin MD , Schaller ME , Fewell GA , Delehaunty KD , Miner TL , Nash WE , Cordes M , Du H , Sun H , Edwards J , Bradshaw-Cordum H , Ali J , Andrews S , Isak A , Vanbrunt A , Nguyen C , Du F , Lamar B , Courtney L , Kalicki J , Ozersky P , Bielicki L , Scott K , Holmes A , Harkins R , Harris A , Strong CM , Hou S , Tomlinson C , Dauphin-Kohlberg S , Kozlowicz-Reilly A , Leonard S , Rohlfing T , Rock SM , Tin-Wollam AM , Abbott A , Minx P , Maupin R , Strowmatt C , Latreille P , Miller N , Johnson D , Murray J , Woessner JP , Wendl MC , Yang SP , Schultz BR , Wallis JW , Spieth J , Bieri TA , Nelson JO , Berkowicz N , Wohldmann PE , Cook LL , Hickenbotham MT , Eldred J , Williams D , Bedell JA , Mardis ER , Clifton SW , Chissoe SL , Marra MA , Raymond C , Haugen E , Gillett W , Zhou Y , James R , Phelps K , Iadanoto S , Bubb K , Simms E , Levy R , Clendenning J , Kaul R , Kent WJ , Furey TS , Baertsch RA , Brent MR , Keibler E , Flicek P , Bork P , Suyama M , Bailey JA , Portnoy ME , Torrents D , Chinwalla AT , Gish WR , Eddy SR , McPherson JD , Olson MV , Eichler EE , Green ED , Waterston RH , Wilson RK
Ref : Nature , 424 :157 , 2003
Abstract : Human chromosome 7 has historically received prominent attention in the human genetics community, primarily related to the search for the cystic fibrosis gene and the frequent cytogenetic changes associated with various forms of cancer. Here we present more than 153 million base pairs representing 99.4% of the euchromatic sequence of chromosome 7, the first metacentric chromosome completed so far. The sequence has excellent concordance with previously established physical and genetic maps, and it exhibits an unusual amount of segmentally duplicated sequence (8.2%), with marked differences between the two arms. Our initial analyses have identified 1,150 protein-coding genes, 605 of which have been confirmed by complementary DNA sequences, and an additional 941 pseudogenes. Of genes confirmed by transcript sequences, some are polymorphic for mutations that disrupt the reading frame.
ESTHER : Hillier_2003_Nature_424_157
PubMedSearch : Hillier_2003_Nature_424_157
PubMedID: 12853948
Gene_locus related to this paper: human-ABHD11 , human-ACHE , human-CPVL , human-DPP6 , human-MEST

Title : The genetics of sensory gating deficits in schizophrenia - Freedman_2003_Curr.Psychiatry.Rep_5_155
Author(s) : Freedman R , Olincy A , Ross RG , Waldo MC , Stevens KE , Adler LE , Leonard S
Ref : Curr Psychiatry Rep , 5 :155 , 2003
Abstract : Sensory gating abnormalities are an early clinical symptom of schizophrenia, and are characterized by a decrease in the brain's normal ability to inhibit the response to unimportant stimuli. Patients appear hypervigilant and have difficulty focusing their attention. A neurobiologic mechanism involved in these difficulties is nicotinic cholinergic modulation of inhibitory neuronal activity in the hippocampus. One measure of sensory gating abnormalities, diminished inhibition of the P50 evoked response to repeated auditory stimuli, has been linked to the chromosome 15q14 locus of the alpha-7-nicotinic receptor gene. This site is one of several that have shown evidence for linkage to schizophrenia, as well as to bipolar disorder, across several studies. Polymorphisms in the core promoter of the gene are associated with schizophrenia and also with diminished inhibition of the P50 response. These genetic data may identify a new pathophysiologic target for drug discovery.
ESTHER : Freedman_2003_Curr.Psychiatry.Rep_5_155
PubMedSearch : Freedman_2003_Curr.Psychiatry.Rep_5_155
PubMedID: 12685995

Title : Recombination in a schizophrenic proband fails to exclude CHRNA7 at chromosome 15q14 -
Author(s) : Leonard S , Freedman R
Ref : Mol Psychiatry , 8 :145 , 2003
PubMedID: 12610645

Title : The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes - Skaletsky_2003_Nature_423_825
Author(s) : Skaletsky H , Kuroda-Kawaguchi T , Minx PJ , Cordum HS , Hillier L , Brown LG , Repping S , Pyntikova T , Ali J , Bieri T , Chinwalla A , Delehaunty A , Delehaunty K , Du H , Fewell G , Fulton L , Fulton R , Graves T , Hou SF , Latrielle P , Leonard S , Mardis E , Maupin R , McPherson J , Miner T , Nash W , Nguyen C , Ozersky P , Pepin K , Rock S , Rohlfing T , Scott K , Schultz B , Strong C , Tin-Wollam A , Yang SP , Waterston RH , Wilson RK , Rozen S , Page DC
Ref : Nature , 423 :825 , 2003
Abstract : The male-specific region of the Y chromosome, the MSY, differentiates the sexes and comprises 95% of the chromosome's length. Here, we report that the MSY is a mosaic of heterochromatic sequences and three classes of euchromatic sequences: X-transposed, X-degenerate and ampliconic. These classes contain all 156 known transcription units, which include 78 protein-coding genes that collectively encode 27 distinct proteins. The X-transposed sequences exhibit 99% identity to the X chromosome. The X-degenerate sequences are remnants of ancient autosomes from which the modern X and Y chromosomes evolved. The ampliconic class includes large regions (about 30% of the MSY euchromatin) where sequence pairs show greater than 99.9% identity, which is maintained by frequent gene conversion (non-reciprocal transfer). The most prominent features here are eight massive palindromes, at least six of which contain testis genes.
ESTHER : Skaletsky_2003_Nature_423_825
PubMedSearch : Skaletsky_2003_Nature_423_825
PubMedID: 12815422
Gene_locus related to this paper: human-NLGN4Y

Title : Comparison of polymorphisms in the alpha7 nicotinic receptor gene and its partial duplication in schizophrenic and control subjects - Gault_2003_Am.J.Med.Genet.B.Neuropsychiatr.Genet_123B_39
Author(s) : Gault J , Hopkins J , Berger R , Drebing C , Logel J , Walton C , Short M , Vianzon R , Olincy A , Ross RG , Adler LE , Freedman R , Leonard S
Ref : American Journal of Medicine Genet B Neuropsychiatr Genet , 123B :39 , 2003
Abstract : The hypothesis that the 15q13-15 region of chromosome 15 contains a gene that contributes to the etiology of schizophrenia is supported by multiple genetic linkage studies. The alpha7 neuronal nicotinic acetylcholine receptor (CHRNA7) gene was selected as the best candidate gene in this region for molecular investigation, based on these linkage findings and biological evidence in both human and rodent models. CHRNA7 receptors are decreased in expression in postmortem brain of schizophrenic subjects. A dinucleotide marker, D15S1360, in intron two of the CHRNA7 gene is genetically linked to an auditory gating deficit found in schizophrenics and half of the first-degree relatives of patients. Single strand conformation polymorphism (SSCP) and sequence analyses of DNA from schizophrenic and control individuals identified 33 variants in the coding region and intron/exon borders of the CHRNA7 gene and its partial duplication, dupCHRNA7; common polymorphisms were mapped. Twenty-one variants were found in the exons, but non-synonymous changes were rare. Although the expression of CHRNA7 is decreased in schizophrenia, the general structure of the remaining receptors is likely to be normal.
ESTHER : Gault_2003_Am.J.Med.Genet.B.Neuropsychiatr.Genet_123B_39
PubMedSearch : Gault_2003_Am.J.Med.Genet.B.Neuropsychiatr.Genet_123B_39
PubMedID: 14582144

Title : Input dysfunction, schizotypy, and genetic models of schizophrenia - Freedman_2002_Schizophr.Res_54_25
Author(s) : Freedman R , Adler LE , Olincy A , Waldo MC , Ross RG , Stevens KE , Leonard S
Ref : Schizophr Res , 54 :25 , 2002
Abstract : Peter Venables proposed that an input dysfunction, which causes the brain to lose its ability to control the flood of sensory information into its higher level processing areas, might be an important pathophysiological mechanism in schizophrenia. The hypothesis was part of his general belief that even the most severe psychopathology arises from aberrations in normal brain psychophysiology. Neurobiological and genetic investigations based on his initial observations include the demonstration that diminished inhibition of the auditory-evoked response to repeated stimuli is a genetically determined deficit, linked to one of the chromosomal loci that is also responsible for the part of the genetically transmitted risk for schizophrenia. Increasing evidence that schizophrenia is a multigenetic illness prompts reconsideration of the nature of schizotypy. Individual genes that convey part of the risk for schizophrenia may be quite common in the general population and cause relatively subtle changes in psychophysiology. Thus, as predicted by Venables, the substrates of schizotypy and schizophrenia may arise from variants in normal brain function.
ESTHER : Freedman_2002_Schizophr.Res_54_25
PubMedSearch : Freedman_2002_Schizophr.Res_54_25
PubMedID: 11853975

Title : Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia - Leonard_2002_Arch.Gen.Psychiatry_59_1085
Author(s) : Leonard S , Gault J , Hopkins J , Logel J , Vianzon R , Short M , Drebing C , Berger R , Venn D , Sirota P , Zerbe G , Olincy A , Ross RG , Adler LE , Freedman R
Ref : Arch Gen Psychiatry , 59 :1085 , 2002
Abstract : BACKGROUND: The alpha7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) has been implicated as a candidate gene for schizophrenia, and for an auditory sensory processing deficit found in the disease, by both genetic linkage at 15q14 and biochemical data. The expression of CHRNA7 is reduced in several brain regions in schizophrenic subjects compared with control subjects. This study presents DNA sequence analysis of the core promoter region for CHRNA7 in schizophrenic and control subjects.
METHODS: Single-strand conformation polymorphism analysis and DNA sequencing were used for mutation screening of the core promoter in the CHRNA7 gene. The sample included subjects from 166 schizophrenic families and 165 controls. Controls had no evidence of current or past psychosis and had auditory evoked potentials recorded.
RESULTS: Multiple polymorphic patterns were identified in the CHRNA7 core promoter in both schizophrenic and control subjects. Functional analysis of polymorphisms indicated that transcription was reduced. The prevalence of functional promoter variants was statistically greater in schizophrenic subjects than in the controls. Presence of an alpha7 promoter polymorphism in controls was associated with failure to inhibit the P50 auditory evoked potential response.
CONCLUSIONS: Although linkage disequilibrium with other genetic alterations cannot be excluded, the CHRNA7 core promoter variants, found in this study, may contribute to a common pathophysiologic feature of schizophrenia.
ESTHER : Leonard_2002_Arch.Gen.Psychiatry_59_1085
PubMedSearch : Leonard_2002_Arch.Gen.Psychiatry_59_1085
PubMedID: 12470124

Title : Are differential behavioral responses to smoking and smoking cessation in schizophrenia related to nicotinic receptor levels? -
Author(s) : Leonard S , Giordano L
Ref : Neuropsychopharmacology , 27 :1082 , 2002
PubMedID: 12464465

Title : Complete genome sequence of Salmonella enterica serovar Typhimurium LT2 - McClelland_2001_Nature_413_852
Author(s) : McClelland M , Sanderson KE , Spieth J , Clifton SW , Latreille P , Courtney L , Porwollik S , Ali J , Dante M , Du F , Hou S , Layman D , Leonard S , Nguyen C , Scott K , Holmes A , Grewal N , Mulvaney E , Ryan E , Sun H , Florea L , Miller W , Stoneking T , Nhan M , Waterston R , Wilson RK
Ref : Nature , 413 :852 , 2001
Abstract : Salmonella enterica subspecies I, serovar Typhimurium (S. typhimurium), is a leading cause of human gastroenteritis, and is used as a mouse model of human typhoid fever. The incidence of non-typhoid salmonellosis is increasing worldwide, causing millions of infections and many deaths in the human population each year. Here we sequenced the 4,857-kilobase (kb) chromosome and 94-kb virulence plasmid of S. typhimurium strain LT2. The distribution of close homologues of S. typhimurium LT2 genes in eight related enterobacteria was determined using previously completed genomes of three related bacteria, sample sequencing of both S. enterica serovar Paratyphi A (S. paratyphi A) and Klebsiella pneumoniae, and hybridization of three unsequenced genomes to a microarray of S. typhimurium LT2 genes. Lateral transfer of genes is frequent, with 11% of the S. typhimurium LT2 genes missing from S. enterica serovar Typhi (S. typhi), and 29% missing from Escherichia coli K12. The 352 gene homologues of S. typhimurium LT2 confined to subspecies I of S. enterica-containing most mammalian and bird pathogens-are useful for studies of epidemiology, host specificity and pathogenesis. Most of these homologues were previously unknown, and 50 may be exported to the periplasm or outer membrane, rendering them accessible as therapeutic or vaccine targets.
ESTHER : McClelland_2001_Nature_413_852
PubMedSearch : McClelland_2001_Nature_413_852
PubMedID: 11677609
Gene_locus related to this paper: salen-OPDB , salti-q8z717 , salty-AES , salty-BIOH , salty-ENTF , salty-FES , salty-IROD , salty-IROE , salty-P74847 , salty-PLDB , salty-STM0332 , salty-STM2547 , salty-STM3079 , salty-STM4506 , salty-STY1441 , salty-STY2428 , salty-STY3846 , salty-yafa , salty-YBFF , salty-ycfp , salty-YFBB , salty-YHET , salty-YJFP , salty-YQIA

Title : The effect of nicotine and haloperidol co-treatment on nicotinic receptor levels in the rat brain - Lee_2001_Brain.Res.Mol.Brain.Res_86_115
Author(s) : Lee MJ , Breese CR , Strook ML , Leonard S
Ref : Brain Research Mol Brain Res , 86 :115 , 2001
Abstract : Genetic and biological data have suggested a role for the neuronal nicotinic acetylcholine receptors in the neuropathophysiology of schizophrenia. Studies in human postmortem brain demonstrate dose-dependent increases in nicotinic receptor binding in normal smokers. We found this upregulation to be reduced in schizophrenic smokers, many of whom had taken typical neuroleptics during their lifetime. The present study examined the hypothesis that typical antipsychotic drug treatment might modulate nicotinic receptor upregulation in a rat model. Nicotine, administered alone or in combination with haloperidol, increased both high and low affinity neuronal nicotinic receptors in a region specific manner. Haloperidol had no generalized effect on basal levels of nicotinic receptor binding or nicotine induced upregulation of nicotinic receptors. However, haloperidol attenuated high affinity nicotinic receptor upregulation in thalamus and low affinity receptor upregulation in hippocampus. These results suggest that haloperidol is not likely to affect nicotinic receptor regulation by smoking in most brain regions.
ESTHER : Lee_2001_Brain.Res.Mol.Brain.Res_86_115
PubMedSearch : Lee_2001_Brain.Res.Mol.Brain.Res_86_115
PubMedID: 11165378

Title : Evidence for the multigenic inheritance of schizophrenia - Freedman_2001_Am.J.Med.Genet_105_794
Author(s) : Freedman R , Leonard S , Olincy A , Kaufmann CA , Malaspina D , Cloninger CR , Svrakic D , Faraone SV , Tsuang MT
Ref : American Journal of Medicine Genet , 105 :794 , 2001
Abstract : Schizophrenia is assumed to have complex inheritance because of its high prevalence and sporadic familial transmission. Findings of linkage on different chromosomes in various studies corroborate this assumption. It is not known whether these findings represent heterogeneous inheritance, in which various ethnic groups inherit illness through different major gene effects, or multigenic inheritance, in which affected individuals inherit several common genetic abnormalities. This study therefore examined inheritance of schizophrenia at different genetic loci in a nationally collected European American and African American sample. Seventy-seven families were previously genotyped at 458 markers for the NIMH Schizophrenia Genetics Initiative. Initial genetic analysis tested a dominant model, with schizophrenia and schizoaffective disorder, depressed type, as the affected phenotype. The families showed one genome-wide significant linkage (Z = 3.97) at chromosome 15q14, which maps within 1 cM of a previous linkage at the alpha 7-nicotinic receptor gene. Chromosome 10p13 showed suggestive linkage (Z = 2.40). Six others (6q21, 9q32, 13q32, 15q24, 17p12, 20q13) were positive, with few differences between the two ethnic groups. The probability of each family transmitting schizophrenia through two genes is greater than expected from the combination of the independent segregation of each gene. Two trait-locus linkage analysis supports a model in which genetic alleles associated with schizophrenia are relatively common in the general population and affected individuals inherit risk for illness through at least two different loci.
ESTHER : Freedman_2001_Am.J.Med.Genet_105_794
PubMedSearch : Freedman_2001_Am.J.Med.Genet_105_794
PubMedID: 11803533

Title : Smoking and mental illness - Leonard_2001_Pharmacol.Biochem.Behav_70_561
Author(s) : Leonard S , Adler LE , Benhammou K , Berger R , Breese CR , Drebing C , Gault J , Lee MJ , Logel J , Olincy A , Ross RG , Stevens K , Sullivan B , Vianzon R , Virnich DE , Waldo M , Walton K , Freedman R
Ref : Pharmacol Biochem Behav , 70 :561 , 2001
Abstract : Patients with mental illness have a higher incidence of smoking than the general population and are the major consumers of tobacco products. This population includes subjects with schizophrenia, manic depression, depression, posttraumatic stress disorder (PTSD), attention-deficit disorder (ADD), and several other less common diseases. Smoking cessation treatment in this group of patients is difficult, often leading to profound depression. Several recent findings suggest that increased smoking in the mentally ill may have an underlying biological etiology. The mental illness schizophrenia has been most thoroughly studied in this regard. Nicotine administration normalizes several sensory-processing deficits seen in this disease. Animal models of sensory deficits have been used to identify specific nicotinic receptor subunits that are involved in these brain pathways, indicating that the alpha 7 nicotinic receptor subunit may play a role. Genetic linkage in schizophrenic families also supports a role for the alpha 7 subunit with linkage at the alpha 7 locus on chromosome 15. Bipolar disorder has some phenotypes in common with schizophrenia and also exhibits genetic linkage to the alpha 7 locus, suggesting that these two disorders may share a gene defect. The alpha 7 receptor is decreased in expression in schizophrenia. [(3)H]-Nicotine binding studies in postmortem brain indicate that high-affinity nicotinic receptors may also be affected in schizophrenia.
ESTHER : Leonard_2001_Pharmacol.Biochem.Behav_70_561
PubMedSearch : Leonard_2001_Pharmacol.Biochem.Behav_70_561
PubMedID: 11796154

Title : Neuronal nicotinic receptors: from structure to function - Leonard_2001_Nicotine.Tob.Res_3_203
Author(s) : Leonard S , Bertrand D
Ref : Nicotine Tob Res , 3 :203 , 2001
Abstract : Molecular identification of the genes and resulting protein sequences for a large number of nicotinic acetylcholine receptor (nAChR) subunits has stimulated numerous studies highlighting their role in several human behaviors including neurological disorders and nicotine addiction. This receptor gene family is likely to be involved in release of multiple neurotransmitters in both brain and periphery that mediate sensitivity and tolerance to nicotine. Recent findings also suggest that alterations in these receptors may lead to neurological diseases, some associated with increased incidence of smoking. This review addresses current knowledge of nicotinic receptor structure, regulation of expression, and function, in both normal and psychiatric subjects.
ESTHER : Leonard_2001_Nicotine.Tob.Res_3_203
PubMedSearch : Leonard_2001_Nicotine.Tob.Res_3_203
PubMedID: 11506765

Title : Linkage disequilibrium for schizophrenia at the chromosome 15q13-14 locus of the alpha7-nicotinic acetylcholine receptor subunit gene (CHRNA7) - Freedman_2001_Am.J.Med.Genet_105_20
Author(s) : Freedman R , Leonard S , Gault JM , Hopkins J , Cloninger CR , Kaufmann CA , Tsuang MT , Farone SV , Malaspina D , Svrakic DM , Sanders A , Gejman P
Ref : American Journal of Medicine Genet , 105 :20 , 2001
Abstract : The transmission/disequilibrium test was used for fine mapping of the linkage of schizophrenia to the chromosome 15q13-14 region, the site of a candidate gene, the alpha7 nicotinic acetylcholine receptor subunit gene (CHRNA7), in parent-child triads from the NIMH Schizophrenia Genetics Initiative families. This candidate gene was identified from neurobiological studies of deficits in schizophrenics of the inhibitory gating of the P50 auditory evoked potential. The neurobiological deficit was also used as a phenotype for subsequent linkage analysis. In the present study, significant genotype-wise disequilibrium (P < 0.007) was found at D15S165, a polymorphic simple sequence marker physically located within 1 megabase of both CHRNA7 and a partially duplicated, expressed sequence that includes exons 5-10 of CHRNA7. Replication of this result was found in an additional set of families. The results support this region as a chromosomal location involved in the genetic transmission of schizophrenia.
ESTHER : Freedman_2001_Am.J.Med.Genet_105_20
PubMedSearch : Freedman_2001_Am.J.Med.Genet_105_20
PubMedID: 11424985

Title : Mecamylamine prevents tolerance but enhances whole brain [3H]epibatidine binding in response to repeated nicotine administration in rats - McCallum_2000_Psychopharmacology.(Berl)_150_1
Author(s) : McCallum SE , Caggiula AR , Booth S , Breese CR , Lee MJ , Donny EC , Leonard S , Sved AF
Ref : Psychopharmacology (Berl) , 150 :1 , 2000
Abstract : RATIONALE: Chronic administration of nicotine in rats results in upregulation of neuronal nicotinic receptors. Upregulation has been proposed to reflect receptor desensitization, which may underlie functional tolerance to nicotine's effects. However, evidence indicates that tolerance and upregulation do not always parallel each other, suggesting that either upregulation does not always reflect desensitization, or mechanisms other than receptor desensitization account for tolerance to nicotine. OBJECTIVES: The present studies examined tolerance to nicotine-induced antinociception and changes in receptor binding after two regimens of intermittent nicotine injections in rats. The role of receptor activation in upregulation and tolerance was also examined by co-administering nicotine with the non-competitive antagonist, mecamylamine.
METHODS: Sprague-Dawley rats were administered a short (once-daily, s.c. for 6 days (0.35 mg/kg)) or long (twice-daily for 11 days (0.66 mg/kg)) series of injections and tolerance to nicotine-induced antinociception and [3H]epibatidine binding in whole brain were measured.
RESULTS: The short series of injections resulted in tolerance to nicotine-induced antinociception, but failed to increase [3H]epibatidine binding. In contrast, the long series of injections resulted in both tolerance and increased receptor binding. Once-daily pairings of mecamylamine (1 mg/kg, s.c.) with nicotine (0.35 mg/kg) for 6 days blocked the development of tolerance, indicating receptor activation is necessary for tolerance to occur. Pairing mecamylamine with nicotine (0.66 mg/kg) twice daily for 11 days blocked tolerance but produced a greater increase in [3H]epibatidine binding than nicotine alone.
CONCLUSIONS: A dissociation of tolerance from receptor upregulation was observed in the present study. The finding that receptor activation may be necessary for tolerance but not upregulation is discussed within the context of possible mechanisms controlling tolerance to nicotine.
ESTHER : McCallum_2000_Psychopharmacology.(Berl)_150_1
PubMedSearch : McCallum_2000_Psychopharmacology.(Berl)_150_1
PubMedID: 10867970

Title : Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia - Breese_2000_Neuropsychopharmacology_23_351
Author(s) : Breese CR , Lee MJ , Adams CE , Sullivan B , Logel J , Gillen KM , Marks MJ , Collins AC , Leonard S
Ref : Neuropsychopharmacology , 23 :351 , 2000
Abstract : Previous studies have suggested that an abnormality in neuronal nicotinic acetylcholine receptor expression or function may be involved in the neuropathophysiology of schizophrenia. [(3)H]-nicotine and [(3)H]-epibatidine binding were compared in postmortem brain from control and schizophrenic subjects with varying smoking histories. In control subjects, increased receptor binding was seen in hippocampus, cortex, and caudate with increasing tobacco use. In contrast, schizophrenic smokers had reduced nicotinic receptor levels in these brain regions compared to control smokers. Chronic haloperidol and nicotine treatment, in the rat, was used to assess neuroleptic effects on receptor up-regulation by nicotine. A significant increase in cortical nicotinic receptors was seen in both nicotine treated as well as haloperidol and nicotine co-treated animals, suggesting that the abnormal regulation of high affinity neuronal nicotinic receptors in schizophrenics following nicotine use was not related to chronic neuroleptic treatment.
ESTHER : Breese_2000_Neuropsychopharmacology_23_351
PubMedSearch : Breese_2000_Neuropsychopharmacology_23_351
PubMedID: 10989262

Title : Sequence and analysis of chromosome 5 of the plant Arabidopsis thaliana - Tabata_2000_Nature_408_823
Author(s) : Tabata S , Kaneko T , Nakamura Y , Kotani H , Kato T , Asamizu E , Miyajima N , Sasamoto S , Kimura T , Hosouchi T , Kawashima K , Kohara M , Matsumoto M , Matsuno A , Muraki A , Nakayama S , Nakazaki N , Naruo K , Okumura S , Shinpo S , Takeuchi C , Wada T , Watanabe A , Yamada M , Yasuda M , Sato S , de la Bastide M , Huang E , Spiegel L , Gnoj L , O'Shaughnessy A , Preston R , Habermann K , Murray J , Johnson D , Rohlfing T , Nelson J , Stoneking T , Pepin K , Spieth J , Sekhon M , Armstrong J , Becker M , Belter E , Cordum H , Cordes M , Courtney L , Courtney W , Dante M , Du H , Edwards J , Fryman J , Haakensen B , Lamar E , Latreille P , Leonard S , Meyer R , Mulvaney E , Ozersky P , Riley A , Strowmatt C , Wagner-McPherson C , Wollam A , Yoakum M , Bell M , Dedhia N , Parnell L , Shah R , Rodriguez M , See LH , Vil D , Baker J , Kirchoff K , Toth K , King L , Bahret A , Miller B , Marra M , Martienssen R , McCombie WR , Wilson RK , Murphy G , Bancroft I , Volckaert G , Wambutt R , Dusterhoft A , Stiekema W , Pohl T , Entian KD , Terryn N , Hartley N , Bent E , Johnson S , Langham SA , McCullagh B , Robben J , Grymonprez B , Zimmermann W , Ramsperger U , Wedler H , Balke K , Wedler E , Peters S , van Staveren M , Dirkse W , Mooijman P , Lankhorst RK , Weitzenegger T , Bothe G , Rose M , Hauf J , Berneiser S , Hempel S , Feldpausch M , Lamberth S , Villarroel R , Gielen J , Ardiles W , Bents O , Lemcke K , Kolesov G , Mayer K , Rudd S , Schoof H , Schueller C , Zaccaria P , Mewes HW , Bevan M , Fransz P
Ref : Nature , 408 :823 , 2000
Abstract : The genome of the model plant Arabidopsis thaliana has been sequenced by an international collaboration, The Arabidopsis Genome Initiative. Here we report the complete sequence of chromosome 5. This chromosome is 26 megabases long; it is the second largest Arabidopsis chromosome and represents 21% of the sequenced regions of the genome. The sequence of chromosomes 2 and 4 have been reported previously and that of chromosomes 1 and 3, together with an analysis of the complete genome sequence, are reported in this issue. Analysis of the sequence of chromosome 5 yields further insights into centromere structure and the sequence determinants of heterochromatin condensation. The 5,874 genes encoded on chromosome 5 reveal several new functions in plants, and the patterns of gene organization provide insights into the mechanisms and extent of genome evolution in plants.
ESTHER : Tabata_2000_Nature_408_823
PubMedSearch : Tabata_2000_Nature_408_823
PubMedID: 11130714
Gene_locus related to this paper: arath-At5g11650 , arath-At5g16120 , arath-at5g18630 , arath-AT5G20520 , arath-At5g21950 , arath-AT5G27320 , arath-CXE15 , arath-F1N13.220 , arath-F14F8.240 , arath-q3e9e4 , arath-q8lae9 , arath-Q8LFB7 , arath-q9ffg7 , arath-q9fij5 , arath-Q9LVU7 , arath-q66gm8 , arath-SCPL34 , arath-B9DFR3 , arath-a0a1p8bcz0

Title : Neuronal nicotinic acetylcholine receptors: from the gene to the disease - Weiland_2000_Behav.Brain.Res_113_43
Author(s) : Weiland S , Bertrand D , Leonard S
Ref : Behavioural Brain Research , 113 :43 , 2000
Abstract : The neuronal nicotinic acetylcholine receptors are excitatory ligand-gated channels. Widely expressed throughout the peripheral and central nervous system, their properties depend upon their subunit composition. Furthermore, genetic studies have revealed a high degree of variation at the genomic level and alternative splicing of the mRNAs coding for these integral membrane proteins. In particular, genes coding for alpha4 and alpha7 subunits harbour a high degree of polymorphisms. Although well characterised at their molecular and functional level, the role of these receptors in the central nervous system remains obscure. Despite accumulating evidence for the participation of nicotinic receptors in disorders of the central nervous system including nicotinic addiction, Parkinson's disease, Alzheimer's disease and Tourette's syndrome, the exact role of these receptors is still speculative. Because most of these phenotypes are complex and genetically heterogeneous, the investigation is difficult. However, in the past few years, significant progress has been made in understanding the contribution of nicotinic acetylcholine receptors to the origin of epilepsies and schizophrenia. By concentrating on the latest results gained for these diseases, we discuss in this review the possible relationships between neuronal nicotinic receptors and neurological and psychiatric disorders.
ESTHER : Weiland_2000_Behav.Brain.Res_113_43
PubMedSearch : Weiland_2000_Behav.Brain.Res_113_43
PubMedID: 10942031

Title : Smoking and schizophrenia: abnormal nicotinic receptor expression - Leonard_2000_Eur.J.Pharmacol_393_237
Author(s) : Leonard S , Breese C , Adams C , Benhammou K , Gault J , Stevens K , Lee M , Adler L , Olincy A , Ross R , Freedman R
Ref : European Journal of Pharmacology , 393 :237 , 2000
Abstract : Biological and genetic evidence suggests a role for the neuronal nicotinic receptors in the neuropathophysiology of schizophrenia. Nicotine normalizes an auditory evoked potential deficit seen in subjects who suffer from the disease. Nicotinic receptors with both high and low affinity for nicotine are decreased in postmortem brain of schizophrenics compared to control subjects. The chromosomal locus of the human alpha-7 gene (15q14) is linked to the gating deficit with a lod of 5.3, and antagonists of the alpha-7 receptor (alpha-bungarotoxin and methyllycaconitine) induce a loss of gating in rodents. We have cloned the human alpha-7 gene and found it to be partially duplicated proximal to the full-length gene. The duplication is expressed in both the brain and in peripheral blood cells of normal subjects, but is missing in some schizophrenic subjects. The results of these studies suggest the presence of abnormal expression and function of the neuronal nicotinic receptor gene family in schizophrenia.
ESTHER : Leonard_2000_Eur.J.Pharmacol_393_237
PubMedSearch : Leonard_2000_Eur.J.Pharmacol_393_237
PubMedID: 10771019

Title : Inhibitory neurophysiological deficit as a phenotype for genetic investigation of schizophrenia - Freedman_2000_Am.J.Med.Genet_97_58
Author(s) : Freedman R , Adams CE , Adler LE , Bickford PC , Gault J , Harris JG , Nagamoto HT , Olincy A , Ross RG , Stevens KE , Waldo M , Leonard S
Ref : American Journal of Medicine Genet , 97 :58 , 2000
Abstract : Many investigators have proposed that biological endophenotypes might facilitate the genetic analysis of schizophrenia. A deficit in the inhibition of the P50 evoked response to repeated auditory stimuli has been characterized as a neurobiological deficit in schizophrenia. This deficit is linked to a candidate gene locus, the locus of the alpha7-nicotinic cholinergic receptor subunit gene on chromosome 15q14. Supportive evidence has been found by other investigators, including: 1) linkage of schizophrenia to the same locus; 2) linkage of bipolar disorder to the locus; and 3) replication of the existence of this neurobiological deficit and its relation to broader neuropsychological deficits in schizophrenia. It is certain that there are many genetic factors in schizophrenia and bipolar disorder; what is needed is a complete and precise description of the contribution of each individual factor to the pathophysiology of these illnesses.
ESTHER : Freedman_2000_Am.J.Med.Genet_97_58
PubMedSearch : Freedman_2000_Am.J.Med.Genet_97_58
PubMedID: 10813805

Title : The alpha7-nicotinic acetylcholine receptor and the pathology of hippocampal interneurons in schizophrenia - Freedman_2000_J.Chem.Neuroanat_20_299
Author(s) : Freedman R , Adams CE , Leonard S
Ref : Journal of Chemical Neuroanatomy , 20 :299 , 2000
Abstract : This paper is a review of a recent findings on the pathology of hippocampal interneurons in schizophrenia, with specific emphasis on a protein expressed by these cells, the alpha7-nicotinic acetylcholine receptor subunit. Convergent information indicates that interneurons in the hippocampus and other forebrain structures are decreased in number and function in subjects with schizophrenia. Among the neurochemical markers that are decreased in the hippocampus are synapsin I, cholecystokinin, somatostatin, glutamic acid decarboxylase, and nitric oxide synthase. GABA uptake sites and the GABA synthetic enzyme glutamic acid decarboxylase are also diminished. Included among these findings is decreased binding of alpha-bungarotoxin, which binds to low-affinity nicotinic acetylcholine receptors, such as the alpha7-nicotinic receptor. Co-labeling experiments in rodents indicate that these markers are expressed on overlapping populations of hippocampal interneurons. Thus, the finding of decreased neurochemical function of hippocampal interneurons is a widely replicated finding, with different groups reporting markedly similar findings using independent post mortem samples and different neurochemical strategies. Decreased alpha-bungarotoxin binding or decreased alpha7-nicotinic receptor immunoreactivity has also been found in the frontal cortex and in the nucleus reticularis thalami of schizophrenic subjects. The alpha7-nicotinic receptor subunit gene on chromosome 15q14 is a site of heritability for schizophrenia and bipolar affective disorder, and in, particular, for a deficit in inhibitory neuronal function associated with these illnesses. Thus, the post mortem data are further supported by psychophysiologic and genetic investigations that indicate a deficit in inhibitory interneuronal function, involving the alpha7-nicotinic receptor. The alpha7-receptor is a ligand-gated ion channel that admits calcium ions into cells, and it has been proposed to have various developmental roles. Its malfunction may be part of the developmental pathogenesis of schizophrenia.
ESTHER : Freedman_2000_J.Chem.Neuroanat_20_299
PubMedSearch : Freedman_2000_J.Chem.Neuroanat_20_299
PubMedID: 11207427

Title : Familial transmission of risk factors in the first-degree relatives of schizophrenic people - Waldo_2000_Biol.Psychiatry_47_231
Author(s) : Waldo MC , Adler LE , Leonard S , Olincy A , Ross RG , Harris JG , Freedman R
Ref : Biological Psychiatry , 47 :231 , 2000
Abstract : Schizophrenia is a complex illness with multiple pathophysiologic factors that contribute to its psychopathology. One strategy to identify these factors is to observe them in isolation from each other, by characterizing their expression in the relatives of schizophrenic probands. By Mendel's second law, each genetic factor should be independently distributed in a sibship, so that each can be observed by itself, uncomplicated by the general problems of the illness. Such independently distributed phenotypes are obviously useful for genetic analyses; however, they can also be considered together, to model how various brain dysfunctions may combine to produce psychoses. In addition to a sensory gating deficit linked to the alpha 7-nicotinic acetylcholine receptor locus, schizophrenics and their families have a number of other deficits, including decreased hippocampal volume on magnetic resonance images and increased plasma levels of the dopamine metabolite homovanillic acid. Although such research is far from complete, a heuristic model combining a sensory gating deficit, decreased hippocampal neuron capacity, and increased dopaminergic neurotransmission is consonant with current understanding of the neuropsychology of schizophrenia.
ESTHER : Waldo_2000_Biol.Psychiatry_47_231
PubMedSearch : Waldo_2000_Biol.Psychiatry_47_231
PubMedID: 10682220

Title : [(3)H]Nicotine binding in peripheral blood cells of smokers is correlated with the number of cigarettes smoked per day - Benhammou_2000_Neuropharmacol_39_2818
Author(s) : Benhammou K , Lee M , Strook M , Sullivan B , Logel J , Raschen K , Gotti C , Leonard S
Ref : Neuropharmacology , 39 :2818 , 2000
Abstract : The principal sites for biological action of tobacco products are thought to be the nicotinic acetylcholine receptors (nAChR). Nicotinic receptor subunit genes, therefore, represent an important gene family for study in nicotine addiction. They are localized in both brain and in the periphery. In brain these receptors appear to function as modulators of synaptic transmission; the function of peripheral receptors is not known. Nicotinic receptor levels in human brain are regulated by smoking in a dose-dependent manner. In peripheral blood, nicotinic receptors are present on both lymphocytes and polymorphonuclear cells (PMN). We have compared [(3)H]nicotine binding in PMN isolated from smokers and non-smokers. [(3)H]nicotine binding was increased in smokers and was correlated, as in brain, with tobacco use. Expression of both mRNA and protein in lymphocytes and PMN, for a subset of nicotinic receptor subunits, suggests that these cell types contain both alpha4beta2 and alpha3beta4 receptors.
ESTHER : Benhammou_2000_Neuropharmacol_39_2818
PubMedSearch : Benhammou_2000_Neuropharmacol_39_2818
PubMedID: 11044752

Title : Decreased bombesin peptide response to cigarette smoking in schizophrenia - Olincy_1999_Neuropsychopharmacology_20_52
Author(s) : Olincy A , Leonard S , Young DA , Sullivan B , Freedman R
Ref : Neuropsychopharmacology , 20 :52 , 1999
Abstract : Schizophrenic patients are extremely heavy tobacco smokers. However, a lower incidence of lung cancer in schizophrenic patients has been observed in comparison to other heavy smokers. Nicotine increases the proliferation of pulmonary neuroendocrine tissue, causing the release of a bombesin-like peptide. Thus, bombesin-like peptide levels in urine may be an indicator of precancerous, cigarette-induced lung damage. Bombesin-like peptide levels of 10 schizophrenic smokers and 11 schizophrenic nonsmokers were compared to those of nonschizophrenic subjects matched for age and pack-years of smoking. The nonschizophrenic smokers showed the expected increase in urinary bombesin-like peptide levels, as compared to nonschizophrenic nonsmokers. Schizophrenic patients had lower bombesin-like peptide levels independent of smoking effects. The mechanism of the difference in bombesin-like peptide levels between schizophrenic patients and nonschizophrenic subjects is unknown, but one possibility involves alteration in the alpha 7-nicotinic acetylcholine receptor, which mediates the growth of some neuroendocrine cell lines in vitro.
ESTHER : Olincy_1999_Neuropsychopharmacology_20_52
PubMedSearch : Olincy_1999_Neuropsychopharmacology_20_52
PubMedID: 9885785

Title : Further investigation of a chromosome 15 locus in schizophrenia: analysis of affected sibpairs from the NIMH Genetics Initiative - Leonard_1998_Am.J.Med.Genet_81_308
Author(s) : Leonard S , Gault J , Moore T , Hopkins J , Robinson M , Olincy A , Adler LE , Cloninger CR , Kaufmann CA , Tsuang MT , Faraone SV , Malaspina D , Svrakic DM , Freedman R
Ref : American Journal of Medicine Genet , 81 :308 , 1998
Abstract : Linkage of a neurophysiological deficit associated with schizophrenia, i.e., the failure to inhibit the auditory P50 response, was previously reported at chromosome 15q14. The marker with the highest pairwise lod score, D15S1360, was isolated from a yeast artificial chromosome containing a candidate gene, the alpha7-nicotinic acetylcholine receptor gene. In the present study, this linkage was further investigated in a subset of the NIMH Genetics Initiative schizophrenia families. These families have not been studied neurophysiologically, as were the families in the original report. Therefore, the DSMIII-R diagnosis of schizophrenia was used as the affected phenotype. Twenty families fulfilled the criteria of at least one sibpair concordant for schizophrenia, along with their two parents or another affected relative outside the nuclear family, available for genotyping. Sibpair analysis showed a significant proportion of D15S1360 alleles shared identical-by-descent (0.58; P < 0.0024). The results further support the involvement of this chromosomal locus in the genetic transmission of schizophrenia.
ESTHER : Leonard_1998_Am.J.Med.Genet_81_308
PubMedSearch : Leonard_1998_Am.J.Med.Genet_81_308
PubMedID: 9674976

Title : Schizophrenia, sensory gating, and nicotinic receptors - Adler_1998_Schizophr.Bull_24_189
Author(s) : Adler LE , Olincy A , Waldo M , Harris JG , Griffith J , Stevens K , Flach K , Nagamoto H , Bickford P , Leonard S , Freedman R
Ref : Schizophr Bull , 24 :189 , 1998
Abstract : A series of human and animal investigations has suggested that altered expression and function of the alpha7-nicotinic cholinergic receptor may be responsible for the auditory sensory gating deficit characterized in schizophrenia patients and their relatives as diminished suppression of an auditory-evoked response (P50) to repeated stimuli. This finding, in conjunction with evidence for familial transmission of this sensory gating deficit, suggests a pathogenic role of the gene for the alpha7-nicotinic receptor in schizophrenia. This article considers the possible effects of this dysfunction in a broader context. Not only is this dysfunction consistent with difficulties in sensory gating, but it might also predispose patients to problems with learning efficiency and accuracy. Such learning problems could underlie schizophrenia patients' delusional thinking, hallucinations, and social dysfunction. In addition, heavy smoking in many schizophrenia patients is consistent with the high concentration of nicotine necessary to activate the receptor and with the receptor's extremely rapid desensitization. Finally, the receptor's possible role in cell growth and differentiation should be considered in connection with developmental deficits and other cellular abnormalities in schizophrenia.
ESTHER : Adler_1998_Schizophr.Bull_24_189
PubMedSearch : Adler_1998_Schizophr.Bull_24_189
PubMedID: 9613620

Title : Nicotinic receptors, smoking and schizophrenia - Leonard_1998_Restor.Neurol.Neurosci_12_195
Author(s) : Leonard S , Gault J , Adams C , Breese CR , Rollins Y , Adler LE , Olincy A , Freedman R
Ref : Restor Neurol Neurosci , 12 :195 , 1998
Abstract : Neuronal nicotinic acetylcholine receptor expression was examined in schizophrenia. The incidence of smoking in schizophrenia is remarkably high and nicotine has been found to normalize an auditory evoked potential deficit seen in most subjects who suffer from this disease. Antagonists and agonists of a specific subset of this receptor family, the alpha7 nicotinic receptor, were found to regulate the gating of filtering of auditory information in both humans and in an animal model. The alpha7 gene has been cloned and a polymorphic dinucleotide repeat near the gene was used for linkage analysis, showing the alpha7 locus to be linked to the P50 deficit. Expression of the alpha7 receptor, which binds nicotine with low affinity, is reduced in the hippocampus of schizophrenics. [3H]-nicotine binding, a measure of the high affinity nicotinic receptors, was also decreased in schizophrenics and does not increase in response to tobacco use, as is seen in control subjects. The results of these studies suggest the presence of abnormal expression and function of the neuronal nicotinic receptor gene family in schizophrenia.
ESTHER : Leonard_1998_Restor.Neurol.Neurosci_12_195
PubMedSearch : Leonard_1998_Restor.Neurol.Neurosci_12_195
PubMedID: 12671315

Title : Acetylcholine activates an alpha-bungarotoxin-sensitive nicotinic current in rat hippocampal interneurons, but not pyramidal cells - Frazier_1998_J.Neurosci_18_1187
Author(s) : Frazier CJ , Rollins YD , Breese CR , Leonard S , Freedman R , Dunwiddie TV
Ref : Journal of Neuroscience , 18 :1187 , 1998
Abstract : The effects of acetylcholine on both pyramidal neurons and interneurons in the area CA1 of the rat hippocampus were examined, using intracellular recording techniques in an in vitro slice preparation. In current-clamp mode, fast local application of acetylcholine (ACh) to the soma of inhibitory interneurons in stratum radiatum resulted in depolarization and rapid firing of action potentials. Under voltage-clamp, ACh produced fast, rapidly desensitizing inward currents that were insensitive to atropine but that were blocked by nanomolar concentrations of the nicotinic alpha7 receptor-selective antagonists alpha-bungarotoxin (alphaBgTx) and methyllycaconitine. Nicotinic receptor antagonists that are not selective for alpha7-containing receptors had little (mecamylamine) or no effect (dihydro-beta-erythroidine) on the ACh-induced currents. Glutamate receptor antagonists had no effect on the ACh-evoked response, indicating that the current was not mediated by presynaptic facilitation of glutamate release. However, the current could be desensitized almost completely by bath superfusion with 100 nM nicotine. In contrast to those actions on interneurons, application of ACh to the soma of CA1 pyramidal cells did not produce a detectable current. Radioligand-binding experiments with [125I]-alphaBgTx demonstrated that stratum radiatum interneurons express alpha7-containing nAChRs, and in situ hybridization revealed significant amounts of alpha7 mRNA. CA1 pyramidal cells did not show specific binding of [125I]-alphaBgTx and only low levels of alpha7 mRNA. These results suggest that, in addition to their proposed presynaptic role in modulating transmitter release, alpha7-containing nAChRs also may play a postsynaptic role in the excitation of hippocampal interneurons. By desensitizing these receptors, nicotine may disrupt this action and indirectly excite pyramidal neurons by reducing GABAergic inhibition.
ESTHER : Frazier_1998_J.Neurosci_18_1187
PubMedSearch : Frazier_1998_J.Neurosci_18_1187
PubMedID: 9454829

Title : Genomic organization and partial duplication of the human alpha7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) - Gault_1998_Genomics_52_173
Author(s) : Gault J , Robinson M , Berger R , Drebing C , Logel J , Hopkins J , Moore T , Jacobs S , Meriwether J , Choi MJ , Kim EJ , Walton K , Buiting K , Davis A , Breese C , Freedman R , Leonard S
Ref : Genomics , 52 :173 , 1998
Abstract : The human alpha7 neuronal nicotinic acetylcholine receptor gene (HGMW-approved symbol CHRNA7) has been characterized from genomic clones. The gene is similar in structure to the chick alpha7 gene with 10 exons and conserved splice junction positions. The size of the human gene is estimated to be larger than 75 kb. A putative promoter 5' of the translation start in exon 1 has been cloned and sequenced. The promoter region lacks a TATA box and has a high GC content (77%). Consensus Sp1, AP-2, Egr-1, and CREB transcription factor binding sites appear to be conserved between bovine and human genes. The alpha7 nAChR gene was found to be partially duplicated, with both loci mapping to the chromosome 15q13 region. A yeast artificial chromosome contig was constructed over a genetic distance of 5 cM that includes both alpha7 loci and the region between them. Four novel exons are described, located in genomic clones containing the partially duplicated gene. The duplicated sequences, including the novel exons, are expressed in human brain.
ESTHER : Gault_1998_Genomics_52_173
PubMedSearch : Gault_1998_Genomics_52_173
PubMedID: 9782083

Title : Comparison of the regional expression of nicotinic acetylcholine receptor alpha7 mRNA and [125I]-alpha-bungarotoxin binding in human postmortem brain - Breese_1997_J.Comp.Neurol_387_385
Author(s) : Breese CR , Adams C , Logel J , Drebing C , Rollins Y , Barnhart M , Sullivan B , Demasters BK , Freedman R , Leonard S
Ref : Journal of Comparative Neurology , 387 :385 , 1997
Abstract : Neuronal nicotinic acetylcholine receptors are expressed in the human central nervous system. A specific subtype of this receptor family, the alpha7 nicotinic acetylcholine receptor, is thought to be the principal alpha-bungarotoxin (alphaBTX)-binding protein in mammalian brain. Although the expression of this receptor subtype has been characterized in rat, no study has specifically compared the expression of both the alpha7 gene and the localization of BTX binding sites in human brain. Expression of alpha7 mRNA and receptor protein in human postmortem brain tissue was examined by in situ hybridization and [125I]-alpha-bungarotoxin autoradiography, respectively, with particular emphasis on regions associated with sensory processing. Regions with high levels of both alpha7 gene expression and [125I]-alphaBTX binding include the nucleus reticularis of the thalamus, the lateral and medial geniculate bodies, the basilar pontine nucleus, the horizontal limb of the diagonal band of Broca, the nucleus basalis of Meynert, and the inferior olivary nucleus. High-to-moderate levels of alpha7 probe hybridization were also seen in the hippocampus and the cerebral cortex; however, there was a reduced or variable degree of [125I]-alphaBTX binding in these regions compared with the level of probe hybridization. In most brain regions, [125I]-alphaBTX binding was localized to neuronal cell bodies similar in morphology to those that exhibited alpha7 hybridization, suggesting that the high-affinity [125I]-alphaBTX binding sites in the human brain are likely to be principally composed of alpha7 receptor subtypes.
ESTHER : Breese_1997_J.Comp.Neurol_387_385
PubMedSearch : Breese_1997_J.Comp.Neurol_387_385
PubMedID: 9335422

Title : Effect of smoking history on [3H]nicotine binding in human postmortem brain - Breese_1997_J.Pharmacol.Exp.Ther_282_7
Author(s) : Breese CR , Marks MJ , Logel J , Adams CE , Sullivan B , Collins AC , Leonard S
Ref : Journal of Pharmacology & Experimental Therapeutics , 282 :7 , 1997
Abstract : Chronic nicotine administration in animal models evokes a dose-dependent increase in brain nicotinic receptor numbers. Genetically determined variability in nicotinic receptor number in different mouse strains has also been reported, which is thought to affect sensitivity to nicotine, as well as the development of tolerance. Humans self-administer nicotine principally in the form of cigarettes and other tobacco products. The present study compared [3H]nicotine binding in human postmortem brain from thalamus and hippocampus of nonsmoking subjects, subjects who had variable life-long smoking histories and subjects who had quit smoking. A significant increase was seen in [3H]nicotine binding in both hippocampus and thalamus of subjects with life-long smoking histories. In the hippocampus, this change resulted from a change in total receptor number (Bmax), with no change in receptor affinity (Kd). There was also a positive correlation between the degree of smoking, as measured by the average reported packs smoked per day, and the number of nicotine binding sites found in both the hippocampus and thalamus, showing that humans exhibit a dose-dependent increase in brain nicotinic receptor binding. Receptor levels in these brain regions after smoking cessation were at or below those found in the control population, which indicated that smoking-induced changes are reversible after cessation of nicotine treatment. These results suggest that increases in nicotinic receptor levels in the human brain may underlie nicotine tolerance and addiction in smokers.
ESTHER : Breese_1997_J.Pharmacol.Exp.Ther_282_7
PubMedSearch : Breese_1997_J.Pharmacol.Exp.Ther_282_7
PubMedID: 9223534

Title : Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus - Freedman_1997_Proc.Natl.Acad.Sci.U.S.A_94_587
Author(s) : Freedman R , Coon H , Myles-Worsley M , Orr-Urtreger A , Olincy A , Davis A , Polymeropoulos M , Holik J , Hopkins J , Hoff M , Rosenthal J , Waldo MC , Reimherr F , Wender P , Yaw J , Young DA , Breese CR , Adams C , Patterson D , Adler LE , Kruglyak L , Leonard S , Byerley W
Ref : Proc Natl Acad Sci U S A , 94 :587 , 1997
Abstract : Inheritance of a defect in a neuronal mechanism that regulates response to auditory stimuli was studied in nine families with multiple cases of schizophrenia. The defect, a decrease in the normal inhibition of the P50 auditory-evoked response to the second of paired stimuli, is associated with attentional disturbances in schizophrenia. Decreased P50 inhibition occurs not only in most schizophrenics, but also in many of their nonschizophrenic relatives, in a distribution consistent with inherited vulnerability for the illness. Neurobiological investigations in both humans and animal models indicated that decreased function of the alpha 7-nicotinic cholinergic receptor could underlie the physiological defect. In the present study, a genome-wide linkage analysis, assuming autosomal dominant transmission, showed that the defect is linked [maximum logarithm of the odds (lod) score = 5.3 with zero recombination] to a dinucleotide polymorphism at chromosome 15q13-14, the site of the alpha 7-nicotinic receptor. Despite many schizophrenics' extremely heavy nicotine use, nicotinic receptors were not previously thought to be involved in schizophrenia. The linkage data thus provide unique new evidence that the alpha 7-nicotinic receptor gene may be responsible for the inheritance of a pathophysiological aspect of the illness.
ESTHER : Freedman_1997_Proc.Natl.Acad.Sci.U.S.A_94_587
PubMedSearch : Freedman_1997_Proc.Natl.Acad.Sci.U.S.A_94_587
PubMedID: 9012828

Title : Nicotinic receptor function in schizophrenia - Leonard_1996_Schizophr.Bull_22_431
Author(s) : Leonard S , Adams C , Breese CR , Adler LE , Bickford P , Byerley W , Coon H , Griffith JM , Miller C , Myles-Worsley M , Nagamoto HT , Rollins Y , Stevens KE , Waldo M , Freedman R
Ref : Schizophr Bull , 22 :431 , 1996
Abstract : Schizophrenia can be partially characterized by deficits in sensory processing. Biochemical, molecular, and genetic studies of one such endophenotype, the P50 auditory-evoked potential gating deficit, suggest that one of the neuronal nicotinic receptors, the alpha 7 nicotinic receptor, may function in an inhibitory neuronal pathway involved in this phenotype. The P50 deficit is normalized in nongating subjects by nicotine. Although most schizophrenia patients are heavy smokers, the effects of nicotine may be transient, as alpha 7 receptors are known to desensitize rapidly. In an animal model of the P50 gating deficit, antagonists of the alpha 7 nicotinic receptor block normal gating of the second of paired auditory stimuli. Regional localization of receptor expression includes areas known to function in sensory filtering. An inhibitory mechanism, in the hippocampus, may involve nicotinic stimulation of gamma-aminobutyric acid (GABA)ergic interneurons, resulting in decreased response to repetitive stimuli. Expression of the alpha 7 receptor is decreased in hippocampal brain tissue, dissected postmortem, from schizophrenia subjects. The P50 deficit is inherited in schizophrenia pedigrees, but it is not sufficient for disease development and thus represents a predisposition factor. Linkage analysis between the P50 deficit in multiplex schizophrenia pedigrees and deoxyribonucleic acid (DNA) markers throughout the genome yielded positive lod scores to DNA markers mapping to a region of chromosome 15 containing the alpha 7 nicotinic receptor gene. Elucidation of possible interactions of the P50 with other factors, known to be important in the etiology of the disease, is important in determining an overall pathobiology of schizophrenia.
ESTHER : Leonard_1996_Schizophr.Bull_22_431
PubMedSearch : Leonard_1996_Schizophr.Bull_22_431
PubMedID: 8873294

Title : Genetic correlation of inhibitory gating of hippocampal auditory evoked response and alpha-bungarotoxin-binding nicotinic cholinergic receptors in inbred mouse strains - Stevens_1996_Neuropsychopharmacology_15_152
Author(s) : Stevens KE , Freedman R , Collins AC , Hall M , Leonard S , Marks MJ , Rose GM
Ref : Neuropsychopharmacology , 15 :152 , 1996
Abstract : One function of the hippocampus is to ascertain the novelty of incoming sensations and encode significant new information into memory. The regulation of response to repeated stimuli may prevent overloading of this function by redundant sensory input. Recent pharmacological studies implicate the role of alpha-bungarotoxin-sensitive nicotinic cholinergic receptors in the inhibition of hippocampal response to repeated auditory stimuli. The number of hippocampal alpha-bungarotoxin-sensitive receptors has a major genetic determinant, as demonstrated by a significant variance between different inbred mouse strains. The purpose of the present study was to determine whether there was a related genetic correlation for the gating of auditory response. Nine inbred mouse strains, representing a continuum of hippocampal alpha-bungarotoxin binding, were tested for the electrophysiological response to repeated auditory stimulation, followed by whole hippocampus membrane alpha-bungarotoxin binding studies. Several parameters of the auditory evoked response showed significant genetic variance over the nine strains, and a significant correlation was found between hippocampal alpha-bungarotoxin binding and both the amplitude of the initial evoked response and its inhibition to repeated auditory stimuli. There was no correlation of the auditory evoked response with high-affinity nicotine binding. These data further support the hypothesis that alpha-bungarotoxin-sensitive nicotinic receptors are involved in the regulation of hippocampal response to repeated auditory stimuli and suggest that this function is genetically controlled.
ESTHER : Stevens_1996_Neuropsychopharmacology_15_152
PubMedSearch : Stevens_1996_Neuropsychopharmacology_15_152
PubMedID: 8840351

Title : Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia - Freedman_1995_Biol.Psychiatry_38_22
Author(s) : Freedman R , Hall M , Adler LE , Leonard S
Ref : Biological Psychiatry , 38 :22 , 1995
Abstract : This study tests the hypothesis that nicotinic cholinergic receptors, including those sensitive to the antagonist alpha-bungarotoxin, are decreased in the hippocampus of schizophrenics. The hypothesis is derived from the finding that alpha-bungarotoxin causes a defect in the inhibitory gating of auditory-evoked potentials in laboratory animals that resembles a defect in auditory sensory gating observed in schizophrenics. Nicotine transiently normalizes this psychophysiological deficit in schizophrenic patients. Postmortem brain tissue was obtained from eight schizophrenic and eight age-matched nonschizophrenic subjects. Sections of the hippocampus were labeled with [125I alpha-bungarotoxin and imagined by autoradiography. Binding of the nicotinic agonist [3H]-cytisine was determined in tissue homogenates. alpha-Bungarotoxin labeled a population of putative interneurons in the hippocampus, primarily in the dentate gyrus and the CA3 region of Ammon's horn. This labeling was significantly decreased in the tissue from the schizophrenic patients, with seven or eight patients below the range of the nonschizophrenic subjects. There was also a significant decrease in the binding of cytisine. The results were not related to generalized hippocampal cell loss, drug exposure at time of death, or smoking history. This initial study suggests that schizophrenic patients have fewer nicotinic receptors in the hippocampus, a condition which may lead to failure of cholinergic activation of inhibitory interneurons, manifest clinically as decreased gating of response to sensory stimulation.
ESTHER : Freedman_1995_Biol.Psychiatry_38_22
PubMedSearch : Freedman_1995_Biol.Psychiatry_38_22
PubMedID: 7548469

Title : Schizophrenia and nicotinic receptors - Freedman_1994_Harv.Rev.Psychiatry_2_179
Author(s) : Freedman R , Adler LE , Bickford P , Byerley W , Coon H , Cullum CM , Griffith JM , Harris JG , Leonard S , Miller C , Myles-Worsley M , Nagamoto HT , Rose G , Waldo M
Ref : Harvard Review of Psychiatry , 2 :179 , 1994
Abstract : Patients with schizophrenia often cannot respond to important features of their environment and filter out irrelevant stimuli. This dysfunction could be related to an underlying defect in inhibition--i.e., the brain's ability to alter its sensitivity to repeated stimuli. One of the neuronal mechanisms responsible for such inhibitory gating involves the activation of cholinergic nicotinic receptors in the hippocampus. These receptors are diminished in many specimens of hippocampal brain tissue obtained postmortem from schizophrenic patients. In living schizophrenic patients, stimulation of cholinergic receptors by nicotine transiently restores inhibitory gating of evoked responses to sensory stimuli. Many people with schizophrenia are heavy smokers, but the properties of the nicotinic receptor favor only short-term activation, which may explain why cigarette smoking is only a transient symptomatic remedy. This paper reviews the clinical phenomenology of inhibitory gating deficits in people with schizophrenia, the neurobiology of such gating mechanisms, and the evidence that some individuals with the disorder may have a heritable deficit in the nicotinic cholinergic receptors involved in this neurobiological function. Inhibitory gating deficits are only partly normalized by neuroleptic drugs and are thus a target for new therapeutic strategies for schizophrenia.
ESTHER : Freedman_1994_Harv.Rev.Psychiatry_2_179
PubMedSearch : Freedman_1994_Harv.Rev.Psychiatry_2_179
PubMedID: 9384901

Title : Enflurane inhibits the function of mouse and human brain phosphatidylinositol-linked acetylcholine and serotonin receptors expressed in Xenopus oocytes - Lin_1993_Mol.Pharmacol_43_941
Author(s) : Lin LH , Leonard S , Harris RA
Ref : Molecular Pharmacology , 43 :941 , 1993
Abstract : Modulation of the inositol 1,4,5-trisphosphate (IP3)-mediated signal transduction pathway by the inhalational anesthetic enflurane was studied in Xenopus oocytes expressing mouse and human cortical mRNA. We found that enflurane significantly inhibited ion currents activated by m1 muscarinic and 5-hydroxytryptamine (5-HT)1c receptors. This inhibition was dependent upon the concentration of acetylcholine or 5-HT, with large inhibition (80-89%) of low concentrations and small inhibition (8-44%) of high concentrations of acetylcholine and 5-HT. Similar effects were found with either mouse or human receptors. To investigate the mechanism of enflurane action, ion currents induced by intracellular injection of guanosine 5'-(3-O-thio)triphosphate and IP3 were examined. Enflurane strongly suppressed the guanosine 5'-(3-O-thio)triphosphate-activated current but not the IP3-activated current. These results suggest that an inhalational anesthetic can disrupt the function of mouse and human brain phosphatidylinositol-linked receptors by selectively inhibiting the guanine nucleotide-binding protein activity.
ESTHER : Lin_1993_Mol.Pharmacol_43_941
PubMedSearch : Lin_1993_Mol.Pharmacol_43_941
PubMedID: 8316225

Title : Alpha-bungarotoxin binding to hippocampal interneurons: immunocytochemical characterization and effects on growth factor expression - Freedman_1993_J.Neurosci_13_1965
Author(s) : Freedman R , Wetmore C , Stromberg I , Leonard S , Olson L
Ref : Journal of Neuroscience , 13 :1965 , 1993
Abstract : The nicotinic cholinergic antagonist alpha-bungarotoxin (alpha-BT) binds throughout the rat hippocampal formation. The binding is displaceable by d-tubocurarine. The most heavily labeled cells are GABA-containing interneurons in the dentate and in Ammon's horn. These neurons have several different morphologies and contain several neuropeptides. alpha-BT-labeled interneurons in the dentate are small cells between the granular and molecular layers that often contain neuropeptide Y. alpha-BT-labeled interneurons in CA1 are medium-sized interneurons, occasionally found in stratum pyramidale, but more often found in stratum radiatum and stratum lacunosum moleculare. These neurons often contain cholecystokinin. The largest alpha-BT-labeled interneurons are found in CA3, in both stratum radiatum and stratum lucidum. These neurons are multipolar and frequently are autofluorescent. They often contain somatostatin or cholecystokinin. These large interneurons have been found to receive medial septal innervation and may also have projections that provide inhibitory feedback directly to the medial septal nucleus. The cholinergic innervation of the hippocampus from the medial septal nucleus is under the trophic regulation of NGF and brain-derived neurotrophic factor, even in adult life. Expression of mRNA for both these factors is increased in CA3 and the dentate after intraventricular administration of alpha-BT, but not after administration of the muscarinic antagonist atropine. alpha-BT-sensitive cholinergic receptors on inhibitory interneurons may be critical to medial septal regulation of the hippocampal activity, including the habituation of response to sensory input.
ESTHER : Freedman_1993_J.Neurosci_13_1965
PubMedSearch : Freedman_1993_J.Neurosci_13_1965
PubMedID: 8478687