Author Report for: Rossner SNo contact information in database for Rossner S
Jaako K, Waniek A, Parik K, Klimaviciusa L, Aonurm-Helm A, Noortoots A, Anier K, Van Elzen R, Gerard M and Zharkovsky A <3 more author(s)> Jaako K, Waniek A, Parik K, Klimaviciusa L, Aonurm-Helm A, Noortoots A, Anier K, Van Elzen R, Gerard M, Lambeir AM, Rossner S, Morawski M, Zharkovsky A (- 3) Ref: Journal of Cell Science, 129:3792, 2016 : PubMed ESTHER: Jaako_2016_J.Cell.Sci_129_3792 PubMedSearch: Jaako 2016 J.Cell.Sci 129 3792 PubMedID: 27566163 Abstract Membrane-associated glycoprotein neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) play an important role in brain plasticity by regulating cell-cell interactions. Here, we demonstrate that the cytosolic serine protease prolyl endopeptidase (PREP) is able to regulate NCAM and PSA-NCAM. Using a SH-SY5Y neuroblastoma cell line with stable overexpression of PREP, we found a remarkable loss of PSA-NCAM, reduced levels of NCAM180 and NCAM140 protein species, and a significant increase in the NCAM immunoreactive band migrating at an apparent molecular weight of 120 kDa in PREP-overexpressing cells. Moreover, increased levels of NCAM fragments were found in the concentrated medium derived from PREP-overexpressing cells. PREP overexpression selectively induced an activation of matrix metalloproteinase-9 (MMP-9), which could be involved in the observed degradation of NCAM, as MMP-9 neutralization reduced the levels of NCAM fragments in cell culture medium. We propose that increased PREP levels promote epidermal growth factor receptor (EGFR) signaling, which in turn activates MMP-9. In conclusion, our findings provide evidence for newly-discovered roles for PREP in mechanisms regulating cellular plasticity through NCAM and PSA-NCAM. Title: Cellular and ultra structural evidence for cytoskeletal localization of prolyl endopeptidase-like protein in neurons Morawski M, Nuytens K, Juhasz T, Zeitschel U, Seeger G, Waelkens E, Regal L, Schulz I, Arendt T and Rossner S <2 more author(s)> Morawski M, Nuytens K, Juhasz T, Zeitschel U, Seeger G, Waelkens E, Regal L, Schulz I, Arendt T, Szeltner Z, Creemers J, Rossner S (- 2) Ref: Neuroscience, 242:128, 2013 : PubMed ESTHER: Morawski_2013_Neurosci_242_128 PubMedSearch: Morawski 2013 Neurosci 242 128 PubMedID: 23485813 Gene_locus related to this paper: human-PREPL Abstract The biochemical properties and subcellular localization of prolyl endopeptidase (PREP) in brain are well characterized and its implications in the realization of cognitive processes and in the pathogenesis of neurodegenerative disorders are a matter of intensive investigation. In contrast, very little is known about its homolog, the PREP-like protein (PREPL). In order to obtain initial hints about the involvement of PREPL in physiological processes, a differential proteomic screen was performed with human skin fibroblasts from controls and patients with PREPL deficiency (hypotonia-cystinuria syndrome). The majority of affected proteins represented cytoskeletal proteins, including caldesmon, tropomyosin alpha3 chain, lamin A, beta-actin, gamma-actin, vimentin and zyxin. Therefore, the analysis of PREPL subcellular localization by confocal laser scanning and electron microscopy in mouse neurons was focused on the cytoskeleton. The co-localization of PREPL with cytoskeletal marker proteins such as beta-actin and microtubulin-associated protein-2 was observed, in addition to the presence of PREPL within Golgi apparatus and growth cones. In the mouse brain, PREPL is neuronally expressed and highly abundant in neocortex, substantia nigra and locus coeruleus. This mirrors to some extent the distribution pattern of PREP and points toward redundant functions of both proteins. In the human neocortex, PREPL immunostaining was found in the cytoplasm and in neuropil, in particular of layer V pyramidal neurons. This staining was reduced in the neocortex of Alzheimer's disease (AD) patients. Moreover, in AD brains, PREPL immunoreactivity was observed in the nucleus and in varicose neuritic processes. Our data indicate physiological functions of PREPL associated with the cytoskeleton, which may be affected under conditions of cytoskeletal degeneration. Title: Prolyl oligopeptidase: a rising star on the stage of neuroinflammation research Penttinen A, Tenorio-Laranga J, Siikanen A, Morawski M, Rossner S, Garcia-Horsman JA Ref: CNS Neurol Disord Drug Targets, 10:340, 2011 : PubMed ESTHER: Penttinen_2011_CNS.Neurol.Disord.Drug.Targets_10_340 PubMedSearch: Penttinen 2011 CNS.Neurol.Disord.Drug.Targets 10 340 PubMedID: 21222623 Abstract Inhibitors of prolyl oligopeptidase have been reported to be neuroprotective, especially in memory loss caused by lesion or disease. This enzyme has also been implicated in neurodegeneration. Although it was initially thought that prolyl oligopeptidase functioned to directly control of neuropeptide levels, emerging evidence points out in part that this peptidase modulates peptides which in turn regulate inflammatory responses. Here we review the recent literature which indicates a direct involvement of prolyl oligopeptidase in several inflammatory diseases. Neuroinflammation generates neurotoxins with a relevant role in neurodegenerative diseases, and it is within this toxin generation where prolyl oligopeptidase might have a role. Title: Distinct glutaminyl cyclase expression in Edinger-Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-Abeta pathology in Alzheimer's disease Morawski M, Hartlage-Rubsamen M, Jager C, Waniek A, Schilling S, Schwab C, McGeer PL, Arendt T, Demuth HU, Rossner S Ref: Acta Neuropathologica, 120:195, 2010 : PubMed ESTHER: Morawski_2010_Acta.Neuropathol_120_195 PubMedSearch: Morawski 2010 Acta.Neuropathol 120 195 PubMedID: 20383514 Abstract Glutaminyl cyclase (QC) was discovered recently as the enzyme catalyzing the pyroglutamate (pGlu or pE) modification of N-terminally truncated Alzheimer's disease (AD) Abeta peptides in vivo. This modification confers resistance to proteolysis, rapid aggregation and neurotoxicity and can be prevented by QC inhibitors in vitro and in vivo, as shown in transgenic animal models. However, in mouse brain QC is only expressed by a relatively low proportion of neurons in most neocortical and hippocampal subregions. Here, we demonstrate that QC is highly abundant in subcortical brain nuclei severely affected in AD. In particular, QC is expressed by virtually all urocortin-1-positive, but not by cholinergic neurons of the Edinger-Westphal nucleus, by noradrenergic locus coeruleus and by cholinergic nucleus basalis magnocellularis neurons in mouse brain. In human brain, QC is expressed by both, urocortin-1 and cholinergic Edinger-Westphal neurons and by locus coeruleus and nucleus basalis Meynert neurons. In brains from AD patients, these neuronal populations displayed intraneuronal pE-Abeta immunoreactivity and morphological signs of degeneration as well as extracellular pE-Abeta deposits. Adjacent AD brain structures lacking QC expression and brains from control subjects were devoid of such aggregates. This is the first demonstration of QC expression and pE-Abeta formation in subcortical brain regions affected in AD. Our results may explain the high vulnerability of defined subcortical neuronal populations and their central target areas in AD as a consequence of QC expression and pE-Abeta formation. Title: Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients Kopelman P, Bryson A, Hickling R, Rissanen A, Rossner S, Toubro S, Valensi P Ref: Int J Obes (Lond), 31:494, 2007 : PubMed ESTHER: Kopelman_2007_Int.J.Obes.(Lond)_31_494 PubMedSearch: Kopelman 2007 Int.J.Obes.(Lond) 31 494 PubMedID: 16953261 Inhibitor(s) related to this paper: Cetilistat Abstract OBJECTIVE: To determine the efficacy, safety and tolerability of cetilistat (ATL-962), a novel inhibitor of gastrointestinal (GI) lipases, in obese patients. DESIGN: Phase II, multicentre, randomized, placebo-controlled, parallel group study. Enrolled patients (N=442) were advised a hypocaloric diet (deficient by 500 kcal per day, 30% of calories from fat) for a 2-week run-in period. Patients who satisfied the entry criteria (N=371) continued on the hypocaloric diet and were randomized to either placebo or one of three different doses of cetilistat (60 mg three times daily t.i.d., 120 mg t.i.d. and 240 mg t.i.d.) for 12 weeks, followed by a 4-week post-treatment follow-up. Safety, tolerability and body weight were assessed, together with other parameters associated with obesity. OUTCOME MEASURES: The primary outcome measure was absolute change in body weight from baseline. Secondary outcomes included the proportion of patients achieving pre-defined weight loss targets, changes from baseline in waist circumference and in blood lipids. GI tolerability criteria were specifically assessed, as was safety. Title: Subcellular localization suggests novel functions for prolyl endopeptidase in protein secretion Schulz I, Zeitschel U, Rudolph T, Ruiz-Carrillo D, Rahfeld JU, Gerhartz B, Bigl V, Demuth HU, Rossner S Ref: Journal of Neurochemistry, 94:970, 2005 : PubMed ESTHER: Schulz_2005_J.Neurochem_94_970 PubMedSearch: Schulz 2005 J.Neurochem 94 970 PubMedID: 16092940 Abstract For a long time, prolyl endopeptidase (PEP) was believed to inactivate neuropeptides in the extracellular space. However, reports on the intracellular activity of PEP suggest additional, as yet unidentified, physiological functions for this enzyme. Here, we demonstrate using biochemical methods of subcellular fractionation, immunocytochemical double-labelling procedures and localization of PEP-enhanced green fluorescent protein fusion proteins that PEP is mainly localized to the perinuclear space, and is associated with the microtubulin cytoskeleton in human neuroblastoma and glioma cell lines. Disassembly of the microtubules by nocodazole treatment disrupts both the fibrillar tubulin and PEP labelling. Furthermore, in a two-hybrid screen, PEP was identified as binding partner of tubulin. These findings indicate novel functions for PEP in axonal transport and/or protein secretion. Indeed, a metabolic labelling approach revealed that both PEP inhibition and PEP antisense mRNA expression result in enhanced peptide/protein secretion from human U-343 glioma cells. Because disturbances in intracellular transport and protein secretion mechanisms are associated with a number of ageing-associated neurodegenerative diseases, cell-permeable PEP inhibitors may be useful for the application in a variety of related clinical conditions. Title: Changes in cortical acetyl-CoA metabolism after selective basal forebrain cholinergic degeneration by 192IgG-saporin Tomaszewicz M, Rossner S, Schliebs R, Cwikowska J, Szutowicz A Ref: Journal of Neurochemistry, 87:318, 2003 : PubMed ESTHER: Tomaszewicz_2003_J.Neurochem_87_318 PubMedSearch: Tomaszewicz 2003 J.Neurochem 87 318 PubMedID: 14511109 Abstract The aim of the present study was to reveal whether reduced cortical cholinergic input affects the acetyl-CoA metabolism in cholinoceptive cortical target regions which may play a causative role for the deficits in cerebral glucose metabolism observed in Alzheimer's disease. The effect of cortical cholinergic denervation produced by a single intracerebroventricular application of the cholinergic immunotoxin 192IgG-saporin, on activities of pyruvate dehydrogenase and adenosine triphosphate (ATP)-citrate lyase as well as on the level of synaptoplasmic and mitochondrial acetyl-CoA and acetylcholine release in cortical target regions was studied. Cholinergic lesion produced 83%, 72% and 32% decreases in the activities of choline acetyltransferase, acetylcholinesterase and ATP-citrate lyase in nerve terminals isolated from rat brain cortex, respectively, but no change in pyruvate dehydrogenase activity. Spontaneous and Ca2+-evoked acetylcholine release from synaptosomes was inhibited by 76% and 73%, respectively, following immunolesion. The lesion-induced 39% decrease of acetyl-CoA level in synaptosomal mitochondria was accompanied by 74% increase in synaptoplasmic fraction. Levels of acetyl-CoA and CoASH assayed in fraction of whole brain mitochondria from lesioned cortex were 61% and 48%, respectively, higher as compared to controls. The data suggest a preferential localization of ATP-citrate lyase in cholinergic nerve terminals, where it may contribute to the transport of acetyl-CoA from the mitochondrial to the cytoplasmic compartment. They provide evidence on differential distribution of acetyl-CoA in subcellular compartments of cholinergic and non-cholinergic nerve terminals. There are also indications that cholinergic activity affects acetyl-CoA level and its intracellular distribution in glial and other non-cholinergic cortical cells. Title: Changes in activity and expression of phosphofructokinase in different rat brain regions after basal forebrain cholinergic lesion Zeitschel U, Schliebs R, Rossner S, Bigl V, Eschrich K, Bigl M Ref: Journal of Neurochemistry, 83:371, 2002 : PubMed ESTHER: Zeitschel_2002_J.Neurochem_83_371 PubMedSearch: Zeitschel 2002 J.Neurochem 83 371 PubMedID: 12423247 Abstract Selective lesion of rat basal forebrain by the cholinergic immunotoxin 192IgG-saporin was used as an animal model to address the question of whether the changes in cortical glucose metabolism observed in patients with Alzheimer's disease may be related to impaired cholinergic transmission. At different times after creating the immunolesion, the isoenzyme pattern and steady-state mRNA levels of the key glycolytic enzyme phosphofructokinase were determined in cortex, hippocampus, basal forebrain and nucleus caudatus. The loss of cholinergic input was accompanied by a persistent decrease in choline acetytransferase and acetylcholine esterase activities in the cortical target areas similar to the cholinergic malfunction seen in Alzheimer's dementia. The basal forebrain lesion induced by the immunotoxin resulted in a transient increase in phosphofructokinase activity peaking on day 7 after inducing the lesion in cortical areas. In parallel, an increased steady-state level of phosphofructokinase mRNA was determined by RT/real-time PCR and in situ hybridization. In contrast, analysis by western blotting and quantitative PCR revealed no changes in the phosphofructokinase isoenzyme pattern after immunolesion. It is concluded that common metabolic mechanisms may underlie the degenerative and repair processes in denervated rat brain and in the diseased Alzheimer's brain. Title: In vivo [125I]-iodobenzovesamicol binding reflects cortical cholinergic deficiency induced by specific immunolesion of rat basal forebrain cholinergic system Sorger D, Schliebs R, Kampfer I, Rossner S, Heinicke J, Dannenberg C, Georgi P Ref: Nucl Med Biol, 27:23, 2000 : PubMed ESTHER: Sorger_2000_Nucl.Med.Biol_27_23 PubMedSearch: Sorger 2000 Nucl.Med.Biol 27 23 PubMedID: 10755642 Abstract In this study, radiolabeled iodobenzovesamicol (IBVM), which is known to bind with high affinity to the vesicular acetylcholine transporter, was tested for its usefulness in imaging cortical cholinergic deficits in vivo. To induce reductions in cortical cholinergic input, the cholinergic immunotoxin 192IgG-saporin was employed. This has been shown to selectively and efficiently destroy basal forebrain cholinergic neurons in rats. The efficiency of the immunolesion was verified by histochemical acetylcholinesterase staining. [125I]-IBVM binding before and after lesioning was measured using autoradiography. Basal forebrain cholinergic cell loss resulted in a considerable reduction in [125I]-IBVM binding in the cholinoceptive target regions, but not in the striatum and cerebellum, brain regions that do not receive a cholinergic input by the basal forebrain cholinergic nuclei, suggesting that [123I]-IBVM has potential in imaging cortical cholinergic deficits in vivo, at least in animals. Title: Glucose metabolism in cholinoceptive cortical rat brain regions after basal forebrain cholinergic lesion Mehlhorn G, Loffler T, Apelt J, Rossner S, Urabe T, Hattori N, Nagamatsu S, Bigl V, Schliebs R Ref: Int J Developmental Neuroscience, 16:675, 1998 : PubMed ESTHER: Mehlhorn_1998_Int.J.Dev.Neurosci_16_675 PubMedSearch: Mehlhorn 1998 Int.J.Dev.Neurosci 16 675 PubMedID: 10198816 Abstract To address the question whether the changes in cortical glucose metabolism observed in patients with Alzheimer's disease are interrelated with, or consequences of, basal forebrain cholinergic cell loss, an experimental approach was employed to produce cortical cholinergic dysfunction in rat brain by administration of the cholinergic immunotoxin 192IgG-saporin. [14C]D-glucose utilization in brain homogenates, D-glucose-displaceable [3H]cytochalasin B binding to glucose transporters (GLUT). Northern and Western analyses, as well as in vivo [14C]2-deoxyglucose autoradiography were used to quantify the regional glucose metabolism. Basal forebrain cholinergic lesion resulted in transient increases in glucose transporter binding in cortical regions displaying reduced acetylcholinesterase activity, already detectable seven days after lesion with peak values around 30 days post lesion. Western analysis revealed that the changes in total glucose transporter binding are mainly due to changes in the GLUT3 subtype only, while the levels of GLUT1 and GLUT3 mRNA (Northern analysis) were not affected by cholinergic lesion. Both immunocytochemistry and in situ hybridization demonstrated preferential localizations of GLUT1 on brain capillaries and GLUT3 on neurons, respectively. A lesion-induced transient decrease in [14C]D-glucose utilization seven days post lesion was detected in the lesion site, whereas cholinoceptive cortical regions were not affected. In vivo [14C]deoxyglucose uptake was transiently increased in cholinoceptive cortical regions and in the lesion site being highest between three to seven days after lesion. The cholinergic lesion-induced transient up-regulation of cortical glucose transporters and deoxyglucose uptake reflects an increased glucose demand in regions depleted by acetylcholine suggesting functional links between cortical cholinergic activity and glucose metabolism in cholinoceptive target regions. Title: Muscarinic acetylcholine receptors activate the acetylcholinesterase gene promoter Nitsch RM, Rossner S, Albrecht C, Mayhaus M, Enderich J, Schliebs R, Wegner M, Arendt T, von der Kammer H Ref: Journal de Physiologie (Paris), 92:257, 1998 : PubMed ESTHER: Nitsch_1998_J.Physiol.Paris_92_257 PubMedSearch: Nitsch 1998 J.Physiol.Paris 92 257 PubMedID: 9789819 Abstract The acetylcholinesterase (AChE) gene promoter contains several overlapping binding sites for Sp1 and Egr-1 transcription factors. Cotransfection experiments and promoter assays showed that Egr-1 can potently activate transcription from the human AChE promoter. Muscarinic acetylcholine receptors (mAChR) rapidly activate, via protein kinase C-mediated signaling, expression of the Egr-1 gene, leading to dramatically increased nuclear concentrations of Egr-1 protein, and to increased binding of Egr-1 to specific DNA recognition sequences. These mAChR-induced increases are followed by increased transcription from the human AChE promoter. In vivo studies with intraventricular infusions of the cholinergic immunotoxin 192 IgG saporin showed more than 80% decrease of AChE activity in cholinergic target areas of the hippocampus and brain cortex. The results are compatible with a combination of decreased AChE activity in degenerating subcortical cholinergic projections, and additional decreases in postsynaptic AChE gene expression. Together our data show that mAChR can activate transcription from the AChE promoter via increased synthesis of Egr-1. The results suggest a feedback mechanism by which the AChE gene is activated by cholinergic neurotransmission, possibly leading to increased formation of AChE protein and accelerated degradation of acetylcholine at cholinergic synapses. This possibility suggests testing of cholinomimetic compounds currently in development for the treatment of Alzheimer's disease for their potential ability to increase AChE gene expression. Title: Cerebrospinal fluid cholinesterases--markers for loss of cholinergic basal forebrain neurons? Rossner S, Bakinde N, Zeitschel U, Schliebs R, Bigl V Ref: Int J Developmental Neuroscience, 16:669, 1998 : PubMed ESTHER: Rossner_1998_Int.J.Dev.Neurosci_16_669 PubMedSearch: Rossner 1998 Int.J.Dev.Neurosci 16 669 PubMedID: 10198815 Abstract The present study was conducted to test the hypothesis that cholinergic basal forebrain neurons are a major source of cerebrospinal fluid (CSF) cholinesterases. To address this question enzyme activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in both CSF and parietal cortex were assayed following selective lesion of basal forebrain cholinergic neurons by a single intracerebroventricular application of the cholinergic immunotoxin 192IgG-saporin. Cholinergic immunolesions led to a dramatic decrease in total AChE activity in parietal cortex, which was due to the specific loss of the G4 molecular form while the activity of the G1 form was increased as compared to nonlesioned animals. In contrast, the total enzyme activity of BChE and its molecular forms were not affected by cholinergic lesion in both parietal cortex and CSF. The data suggest, that cholinergic basal forebrain neurons are seemingly not a major source of cholinesterases in the CSF, and do not provide any evidence for using CSF cholinesterases as a diagnostic marker of basal forebrain cholinergic cell loss in humans. Title: Basal forebrain cholinergic immunolesion by 192IgG-saporin: evidence for a presynaptic location of subpopulations of alpha (2)- and beta- adrenergic as well as 5-HT2A receptors on cortical cholinergic terminals Heider M, Schliebs R, Rossner S, Bigl V Ref: Neurochem Res, 22:957, 1997 : PubMed ESTHER: Heider_1997_Neurochem.Res_22_957 PubMedSearch: Heider 1997 Neurochem.Res 22 957 PubMedID: 9239751 Abstract To study whether the changes in cortical noradrenergic and serotonergic mechanisms observed in patients with Alzheimer's disease are the consequence of reduced cortical cholinergic activity, a novel colinergic immunotoxin (conjugate of the monoclonal antibody 192IgG against the lower affinity nerve growth factor receptor with the cytotoxic protein saporin, 192IgG-saporin) was used to produce a specific and selective loss of cholinergic cells in rat basal forebrain nuclei. To correlate the responses to cholinergic immunolesion in cholinoceptive cortical target regions with cholinergic hypoactivity, quantitative receptor autoradiography to measure adrenoceptors and 5-hydroxytryptamine (5-HT) receptor subtypes, and histochemistry to estimate acetylcholinesterase activity, were performed in adjacent brain sections. alpha 1-adrenoceptor and 5-HT1A receptor binding were not affected by cholinergic immunolesion in any of the cortical and hippocampal regions studied. However, cholinergic immunolesion resulted in significantly reduced alpha 2- and beta-adrenoceptor as well as 5-HT2A receptor binding in a number of cortical and hippocampal regions displaying a reduced activity of acetylcholinesterase, already detectable seven days after a single injection of 192IgG-saporin and persisting up to three months post lesion without any significant recovery. The data suggest that at least a subpopulation of alpha 2- and beta-adrenoceptor as well 5-HT2A receptor subtype is present on cortical and hippocampal cholinergic terminals originating in the basal forebrain. The lesion-induced receptor changes suggest that the alterations in cortical 5-HT2 receptor binding observed in patients with Alzheimer's disease might be secondary to cholinergic deficits. Title: Immunolesion by 192IgG-saporin of rat basal forebrain cholinergic system: a useful tool to produce cortical cholinergic dysfunction Schliebs R, Rossner S, Bigl V Ref: Prog Brain Res, 109:253, 1996 : PubMed ESTHER: Schliebs_1996_Prog.Brain.Res_109_253 PubMedSearch: Schliebs 1996 Prog.Brain.Res 109 253 PubMedID: 9009714 Abstract Cholinergic lesion paradigms have been used to study the role of the cholinergic system in cortical arousal and cognitive function, and its implication in cognitive deficits that occur in Alzheimer's disease. In the last few years an increasing number of studies have applied neurotoxins including excitotoxins or cholinotoxins (e.g. AF64A) by stereotaxic injection into the Nbm to produce reductions in cortical cholinergic activity. One of the most serious limitations of these lesion paradigms is the fact that basal forebrain cholinergic neurons are always intermingled with populations of noncholinergic cells and that the cytotoxins used are far from being selective to cholinergic cells. Excitoxins when infused directly into the Nbm destroy non-specifically cell bodies but spare axons passing the injection site, whereas the specificity of AF64A to destroy cholinergic neurons depends on both the dosage applied and the site of injection. Recently, a monoclonal antibody to the low-affinity nerve growth factor (NGF) receptor, 192IgG, coupled to a cytotoxin, saporin, has been described as an efficient and selective immunotoxin for the NGF-receptor bearing cholinergic neurons in rat basal forebrain. Intraventricular administration of the 192IgG-saporin conjugate appears to induce a nearly complete and specific lesion of neocortical and hippocampal cholinergic afferents. Other neuronal systems in the basal forebrain are spared by the immunotoxin. Electrolytic, ibotenic acid, and cholinergic immunotoxic lesions of cholinergic basal forebrain nuclei resulted in slightly different effects on cortical cholinergic markers: Electrolytic lesion of the Nbm did not change M1-mAChR but resulted in reduced M2-mAChR in frontal and parietal cortices 1 week after lesion. Ibotenic acid lesion of the nucleus basalis did not alter M1-mAChR in any cortical region but led to enhanced M2-mAChR binding in the parietal cortex only. When applying the cholinergic immunotoxin 192IgG-saporin, both M1- and M2-mAChR binding sites were increased in a number of cortical areas 1 week after lesion. This comparison suggests that possibly the destruction of non-cholinergic basal forebrain cells by ibotenic acid and electrolytic lesion, might partly contribute to these different cortical effects. NMDA receptor binding was markedly reduced and AMPA, kainate, and GABAA receptor binding has been significantly increased in cortical regions displaying a reduced activity of AChE and decreased levels of high-affinity choline uptake sites due to immunolesion of the basal forebrain cholinergic system. Equivalent changes in cortical glutamate and GABA receptor subtype levels have been observed 7 days after electrolytic or ibotenic acid lesion of the Nbm. The data suggest that cholinergic immunolesion by 192IgG-saporin exhibits a valuable tool to produce specific cholinergic deficits in rats, which can be used as a model to study the effect of treatment with various drugs for compensating the impaired cortical cholinergic input. Title: 192IgG-saporin-induced immunotoxic lesions of cholinergic basal forebrain system differentially affect glutamatergic and GABAergic markers in cortical rat brain regions Rossner S, Schliebs R, Bigl V Ref: Brain Research, 696:165, 1995 : PubMed ESTHER: Rossner_1995_Brain.Res_696_165 PubMedSearch: Rossner 1995 Brain.Res 696 165 PubMedID: 8574666 Abstract To study the effect of reduced cortical cholinergic activity on GABAergic and glutamatergic mechanisms in cholinoceptive cortical target regions a novel cholinergic immunotoxin (conjugate of the monoclonal antibody 192IgG against the low-affinity nerve growth factor receptor with the cytotoxic protein saporin) was applied, which specifically and selectively destroys cholinergic cells in rat basal forebrain nuclei. To correlate the responses to cholinergic immunolesion in cholinoceptive cortical target regions with cholinergic hypoactivity, quantitative receptor autoradiography to measure NMDA, AMPA and kainate glutamate receptor subtypes, GABAA and benzodiazepine receptors as well as choline uptake sites, and histochemistry to estimate acetylcholinesterase activity were performed in adjacent brain sections. One week after a single intraventricular injection of 4 micrograms of 192IgG-saporin, NMDA receptor binding was markedly reduced in cortical regions displaying a reduced activity of acetylcholinesterase and high-affinity choline uptake sites as a consequence of cholinergic lesion, whereas AMPA and kainate binding sites were significantly increased in these regions. Muscimol binding to GABAA receptors was increased in the caudal portions of frontal and parietal cortices as well as occipital and temporal cortex as compared to the corresponding brain regions from vehicle-injected control rats. Binding levels of benzodiazepine receptors were not affected by the lesion in any of the cortical regions studied. The differential changes in glutamate and GABA receptor subtypes following cholinergic immunolesion might be regarded as the consequence of a cortical reorganization compensating for the reduced cholinergic presynaptic input. The data further suggest that presynaptic cortical cholinergic deficits might affect both glutamatergic and GABAergic functions with different intensity and different directions. Title: Development of laminar expression of the m2 muscarinic cholinergic receptor gene in rat visual cortex and the effect of monocular visual deprivation Rossner S, Kumar A, Witzemann V, Schliebs R Ref: Brain Research Developmental Brain Research, 77:55, 1994 : PubMed ESTHER: Rossner_1994_Brain.Res.Dev.Brain.Res_77_55 PubMedSearch: Rossner 1994 Brain.Res.Dev.Brain.Res 77 55 PubMedID: 8131263 Abstract The postnatal development of laminar pattern of the m2 muscarinic acetylcholine receptor subtype mRNA in the visual cortex of both normally raised and monocularly deprived rats (one eyelid sutured at the age of 11 days) was studied using in situ hybridization histochemistry and computer-assisted image analysis. In normally raised rats, on birth, the m2 transcript was found to be more concentrated in the superficial zones of the cortex. This laminar pattern alters to a more homogeneous distribution of the label throughout the cortex already detectable on day 7. From day 10 onwards a bimodal laminar pattern gradually develops with increased mRNA levels in layer IV and upper layer VI. From postnatal day 21 onwards the hybridization peak in layer VI decreases as compared to the peak level in layer IV resulting in an adult distribution with highest labeling in layer IV, low labeling in layer I to III and moderate labeling in layers V and VI. Monocular deprivation results in decreased m2 mRNA levels in visual cortical layers IV-VI in both deprived and non-deprived cortices already detectable at the age of 18 days and persisting up to the age of 21 days; but this effect disappears following further deprivation until adulthood. The data suggest that the changes in m2 receptor level from a more homogeneous distribution to a bimodal pattern during postnatal development seem to be related to synaptogenesis and final tuning of connectional pattern within the rat visual cortex. Title: Ibotenic acid lesion of nucleus basalis magnocellularis differentially affects cholinergic, glutamatergic and GABAergic markers in cortical rat brain regions Rossner S, Schliebs R, Bigl V Ref: Brain Research, 668:85, 1994 : PubMed ESTHER: Rossner_1994_Brain.Res_668_85 PubMedSearch: Rossner 1994 Brain.Res 668 85 PubMedID: 7704621 Abstract The present study was undertaken to study the effect of reduced cortical cholinergic activity on gamma-aminobutyric acid (GABA)ergic and glutamatergic mechanisms in cholinoceptive cortical target regions which are assumed to play an important role for realizing cognitive functions. The densities of cortical muscarinic cholinergic receptor subtypes and corresponding receptor genes m1 through m4, N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) and kainate glutamate receptor subtypes as well as GABAA and benzodiazepine receptors were measured in rats 1 week after unilateral ibotenic acid lesion of the nucleus basalis magnocellularis (Nbm) applying quantitative receptor autoradiography and in situ hybridization. Ibotenic acid lesion resulted in a striking loss of acetylcholinesterase (AChE) staining in the lesioned Nbm which is associated with a 60% decrease in AChE staining and a 30% reduction in [3H]hemicholinium-3 binding in frontal and parietal cortical regions as well fore- and hindlimb areas ipsilateral to the lesion, being more prominent in the more rostral cortical regions. M1-muscarinic cholinergic receptor binding was not changed in any of the cortical regions studied 1 week after lesion. M2-muscarinic receptor binding levels are slightly increased in the parietal cortex only. The lesion-induced increase in parietal cortical M2-muscarinic receptor binding is complemented by an increase in the hybridization signal for the corresponding m4-mRNA transcript. In cortical regions displaying a reduced activity of AChE and decreased levels of high-affinity choline uptake sites due to forebrain cholinergic lesion, NMDA receptor binding was markedly reduced in comparison to the unlesioned brain side whereas AMPA and kainate binding has been significantly increased in these regions. Muscimol binding to GABAA receptors was increased in the rostral portions of frontal and parietal cortices as compared with the unlesioned brain side. Binding levels of benzodiazepine receptors were not affected by the lesion in any of the cortical regions studied. The differential changes in glutamate and GABA receptor subtypes following lesion might be regarded as the consequence of a cortical reorganization compensating for the reduced cholinergic presynaptic input. The data further suggest that presynaptic cortical cholinergic deficits might affect both glutamatergic and GABAergic functions with different intensity and different directions. Title: Laminar expression of m1-, m3- and m4-muscarinic cholinergic receptor genes in the developing rat visual cortex using in situ hybridization histochemistry. Effect of monocular visual deprivation Rossner S, Kues W, Witzemann V, Schliebs R Ref: Int J Developmental Neuroscience, 11:369, 1993 : PubMed ESTHER: Rossner_1993_Int.J.Dev.Neurosci_11_369 PubMedSearch: Rossner 1993 Int.J.Dev.Neurosci 11 369 PubMedID: 8356903 Abstract The postnatal development of laminar pattern of m1-, m3- and m4-mRNA-muscarinic acetylcholine receptor subtypes in the visual cortex of both normally raised and monocularly deprived rats (one eyelid sutured at the age of 11 days) was studied using in situ hybridization histochemistry and computer-assisted image analysis. From birth until day 15 the level of m1-receptor transcript in layer II/III increases markedly as compared to deeper layers. From day 15 up to day 18 a transient bimodal pattern develops with peaks in layers II/III and VI. Already on day 35 a more homogeneous distribution of m1-receptor mRNA level is detectable persisting until adulthood. In contrast, the m3-receptor mRNA shows already at birth a bimodal distribution with peaks in layers II/III and VI. Further development until adulthood results in transient changes in the ratio of the mRNA levels in these layers. In the adult visual cortex a similar laminar pattern as at birth is observed. From day 1 up to day 10 a relative increase in the mRNA level of the m4-receptor in layers II to IV is observed. From day 10 until day 15 a bimodal distribution of receptor mRNA develops with peaks in layers III and VI which is similar to the adult stage. However, between days 18 and 35 a shift in the laminar receptor mRNA distribution occurs resulting in peaks in layers IV and VI. The labeling of the m5-receptor transcript in rat visual cortex was very weak and did not show any alteration with age. Unilateral eyelid closure from postnatal day 11 resulted in transient changes in the laminar distribution of m3- and m4-receptor mRNA between postnatal days 18 and 25, whereas the development of the laminar pattern of the m1-receptor mRNA was not affected regardless of the length of visual deprivation. The distinct laminar developmental pattern of mRNA muscarinic receptor subtypes in rat visual cortex suggests specific roles of the muscarinic receptor subtypes during the first weeks of postnatal maturation of visual function. | |||||||
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