Tabuchi K

References (12)

Title : Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice - Yoshida_2021_Nat.Commun_12_1848
Author(s) : Yoshida T , Yamagata A , Imai A , Kim J , Izumi H , Nakashima S , Shiroshima T , Maeda A , Iwasawa-Okamoto S , Azechi K , Osaka F , Saitoh T , Maenaka K , Shimada T , Fukata Y , Fukata M , Matsumoto J , Nishijo H , Takao K , Tanaka S , Okabe S , Tabuchi K , Uemura T , Mishina M , Mori H , Fukai S
Ref : Nat Commun , 12 :1848 , 2021
Abstract : Neuroligin 3 (NLGN3) and neurexins (NRXNs) constitute a canonical transsynaptic cell-adhesion pair, which has been implicated in autism. In autism spectrum disorder (ASD) development of sociality can be impaired. However, the molecular mechanism underlying NLGN3-mediated social development is unclear. Here, we identify non-canonical interactions between NLGN3 and protein tyrosine phosphatase delta (PTPdelta) splice variants, competing with NRXN binding. NLGN3-PTPdelta complex structure revealed a splicing-dependent interaction mode and competition mechanism between PTPdelta and NRXNs. Mice carrying a NLGN3 mutation that selectively impairs NLGN3-NRXN interaction show increased sociability, whereas mice where the NLGN3-PTPdelta interaction is impaired exhibit impaired social behavior and enhanced motor learning, with imbalance in excitatory/inhibitory synaptic protein expressions, as reported in the Nlgn3 R451C autism model. At neuronal level, the autism-related Nlgn3 R451C mutation causes selective impairment in the non-canonical pathway. Our findings suggest that canonical and non-canonical NLGN3 pathways compete and regulate the development of sociality.
ESTHER : Yoshida_2021_Nat.Commun_12_1848
PubMedSearch : Yoshida_2021_Nat.Commun_12_1848
PubMedID: 33758193
Gene_locus related to this paper: mouse-3neur

Title : An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum - Lai_2021_Front.Neural.Circuits_15_676891
Author(s) : Lai ESK , Nakayama H , Miyazaki T , Nakazawa T , Tabuchi K , Hashimoto K , Watanabe M , Kano M
Ref : Front Neural Circuits , 15 :676891 , 2021
Abstract : Neuroligin is a postsynaptic cell-adhesion molecule that is involved in synapse formation and maturation by interacting with presynaptic neurexin. Mutations in neuroligin genes, including the arginine to cystein substitution at the 451st amino acid residue (R451C) of neuroligin-3 (NLGN3), have been identified in patients with autism spectrum disorder (ASD). Functional magnetic resonance imaging and examination of post-mortem brain in ASD patients implicate alteration of cerebellar morphology and Purkinje cell (PC) loss. In the present study, we examined possible association between the R451C mutation in NLGN3 and synaptic development and function in the mouse cerebellum. In NLGN3-R451C mutant mice, the expression of NLGN3 protein in the cerebellum was reduced to about 10% of the level of wild-type mice. Elimination of redundant climbing fiber (CF) to PC synapses was impaired from postnatal day 10-15 (P10-15) in NLGN3-R451C mutant mice, but majority of PCs became mono-innervated as in wild-type mice after P16. In NLGN3-R451C mutant mice, selective strengthening of a single CF relative to the other CFs in each PC was impaired from P16, which persisted into juvenile stage. Furthermore, the inhibition to excitation (I/E) balance of synaptic inputs to PCs was elevated, and calcium transients in the soma induced by strong and weak CF inputs were reduced in NLGN3-R451C mutant mice. These results suggest that a single point mutation in NLGN3 significantly influences the synapse development and refinement in cerebellar circuitry, which might be related to the pathogenesis of ASD.
ESTHER : Lai_2021_Front.Neural.Circuits_15_676891
PubMedSearch : Lai_2021_Front.Neural.Circuits_15_676891
PubMedID: 34262438
Gene_locus related to this paper: human-NLGN3

Title : Functions of synapse adhesion molecules neurexin\/neuroligins and neurodevelopmental disorders - Cao_2017_Neurosci.Res_116_3
Author(s) : Cao X , Tabuchi K
Ref : Neurosci Res , 116 :3 , 2017
Abstract : Neurexins and neuroligins are two distinct families of single-pass transmembrane proteins localized at pre- and postsynapses, respectively. They trans-synaptically interact with each other and induce synapse formation and maturation. Common variants and rare mutations, including copy number variations, short deletions, and single or small nucleotide changes in neurexin and neuroligin genes have been linked to the neurodevelopmental disorders, such as autism spectrum disorders (ASDs). In this review, we summarize the structure and basic synaptic function of neurexins and neuroligins, followed by behaviors and synaptic phenotypes of knock-in and knock-out mouse of these family genes. From the studies of these mice, it turns out that the effects of neurexins and neuroligins are amazingly neural circuit dependent, even within the same brain region. In addition, neurexins and neuroligins are commonly involved in the endocannabinoid signaling. These finding may provide not only insight into understanding the pathophysiology, but also the concept for strategy of therapeutic intervention for ASDs.
ESTHER : Cao_2017_Neurosci.Res_116_3
PubMedSearch : Cao_2017_Neurosci.Res_116_3
PubMedID: 27664583

Title : Distortion of the normal function of synaptic cell adhesion molecules by genetic variants as a risk for autism spectrum disorders - Baig_2017_Brain.Res.Bull_129_82
Author(s) : Baig DN , Yanagawa T , Tabuchi K
Ref : Brain Research Bulletin , 129 :82 , 2017
Abstract : Synaptic cell adhesion molecules (SCAMs) are a functional category of cell adhesion molecules that connect pre- and postsynapses by the protein-protein interaction via their extracellular cell adhesion domains. Countless numbers of common genetic variants and rare mutations in SCAMs have been identified in the patients with autism spectrum disorders (ASDs). Among these, NRXN and NLGN family proteins cooperatively function at synaptic terminals both of which genes are strongly implicated as risk genes for ASDs. Knock-in mice carrying a single rare point mutation of NLGN3 (NLGN3 R451C) discovered in the patients with ASDs display a deficit in social interaction and an enhancement of spatial learning and memory ability reminiscent of the clinical phenotype of ASDs. NLGN4 knockout (KO) and NRXN2alpha KO mice also show a deficit in sociability as well as some specific neuropsychiatric behaviors. In this review, we selected NRXNs/NLGNs, CNTNAP2/CNTNAP4, CNTN4, ITGB3, and KIRREL3 as strong ASD risk genes based on SFARI score and summarize the protein structures, functions at synapses, representative discoveries in human genetic studies, and phenotypes of the mutant model mice in light of the pathophysiology of ASDs.
ESTHER : Baig_2017_Brain.Res.Bull_129_82
PubMedSearch : Baig_2017_Brain.Res.Bull_129_82
PubMedID: 27743928

Title : [Synapse maturation and autism: learning from neuroligin model mice] - Tabuchi_2014_Nihon.Shinkei.Seishin.Yakurigaku.Zasshi_34_1
Author(s) : Tabuchi K , Hang W , Asgar NF , Pramanik G
Ref : Nihon Shinkei Seishin Yakurigaku Zasshi , 34 :1 , 2014
Abstract : Autism is a neurodevelopmental disorder characterized by impairments in social interaction, communication, and restricted and repetitive behavior. Synaptic defects have been implicated in autism; nevertheless, the cause is still largely unknown. A mutation that substitutes cysteine for arginine at residue 451 of Neuroligin-3 (R451C) is the first monogenic mutation identified in idiopathic autism patients. To study the relationship between this mutation and autism, we generated knock-in mice that recapitulated this mutation. The knock-in mice were born and grew up normally without showing any major physical phenotypes, but showed a deficit in social interaction. We studied synaptic function in the layer II/III pyramidal neurons in the somatosensory cortex and found inhibitory synaptic transmission was enhanced in the knock-in mice. The administration of GABA blocker rescued social interaction, suggesting that this caused autistic behavior in these mice. We also found, by Morris water maze test, that spatial learning and memory were significantly enhanced in the knock-in mice. Electrophysiology in the CA1 region of the hippocampus revealed that LTP, the NMDA/AMPA ratio, and NR2B function were enhanced, indicating that synaptic maturation was impaired in the knock-in mice. This may cause the deficit in social behavior and extraordinary memory ability occasionally seen in autistic patients.
ESTHER : Tabuchi_2014_Nihon.Shinkei.Seishin.Yakurigaku.Zasshi_34_1
PubMedSearch : Tabuchi_2014_Nihon.Shinkei.Seishin.Yakurigaku.Zasshi_34_1
PubMedID: 25069265

Title : Enhanced synapse remodelling as a common phenotype in mouse models of autism - Isshiki_2014_Nat.Commun_5_4742
Author(s) : Isshiki M , Tanaka S , Kuriu T , Tabuchi K , Takumi T , Okabe S
Ref : Nat Commun , 5 :4742 , 2014
Abstract : Developmental deficits in neuronal connectivity are considered to be present in patients with autism spectrum disorders (ASDs). Here we examine this possibility by using in vivo spine imaging in the early postnatal cortex of ASD mouse models. Spines are classified by the presence of either the excitatory postsynaptic marker PSD-95 or the inhibitory postsynaptic marker gephyrin. ASD mouse models show consistent upregulation in the dynamics of PSD-95-positive spines, which may subsequently contribute to stable synaptic connectivity. In contrast, spines receiving inputs from the thalamus, detected by the presence of gephyrin clusters, are larger, highly stable and unaffected in ASD mouse models. Importantly, two distinct mouse models, human 15q11-13 duplication and neuroligin-3 R451C point mutation, show highly similar phenotypes in spine dynamics. This selective impairment in dynamics of PSD-95-positive spines receiving intracortical projections may be a core component of early pathological changes and be a potential target of early intervention.
ESTHER : Isshiki_2014_Nat.Commun_5_4742
PubMedSearch : Isshiki_2014_Nat.Commun_5_4742
PubMedID: 25144834

Title : Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling - Budreck_2013_Proc.Natl.Acad.Sci.U.S.A_110_725
Author(s) : Budreck EC , Kwon OB , Jung JH , Baudouin S , Thommen A , Kim HS , Fukazawa Y , Harada H , Tabuchi K , Shigemoto R , Scheiffele P , Kim JH
Ref : Proc Natl Acad Sci U S A , 110 :725 , 2013
Abstract : Despite the pivotal functions of the NMDA receptor (NMDAR) for neural circuit development and synaptic plasticity, the molecular mechanisms underlying the dynamics of NMDAR trafficking are poorly understood. The cell adhesion molecule neuroligin-1 (NL1) modifies NMDAR-dependent synaptic transmission and synaptic plasticity, but it is unclear whether NL1 controls synaptic accumulation or function of the receptors. Here, we provide evidence that NL1 regulates the abundance of NMDARs at postsynaptic sites. This function relies on extracellular, NL1 isoform-specific sequences that facilitate biochemical interactions between NL1 and the NMDAR GluN1 subunit. Our work uncovers NL1 isoform-specific cis-interactions with ionotropic glutamate receptors as a key mechanism for controlling synaptic properties.
ESTHER : Budreck_2013_Proc.Natl.Acad.Sci.U.S.A_110_725
PubMedSearch : Budreck_2013_Proc.Natl.Acad.Sci.U.S.A_110_725
PubMedID: 23269831

Title : An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus - Etherton_2011_EMBO.J_30_2908
Author(s) : Etherton MR , Tabuchi K , Sharma M , Ko J , Sudhof TC
Ref : EMBO Journal , 30 :2908 , 2011
Abstract : Neuroligins are evolutionarily conserved postsynaptic cell-adhesion molecules that function, at least in part, by forming trans-synaptic complexes with presynaptic neurexins. Different neuroligin isoforms perform diverse functions and exhibit distinct intracellular localizations, but contain similar cytoplasmic sequences whose role remains largely unknown. Here, we analysed the effect of a single amino-acid substitution (R704C) that targets a conserved arginine residue in the cytoplasmic sequence of all neuroligins, and that was associated with autism in neuroligin-4. We introduced the R704C mutation into mouse neuroligin-3 by homologous recombination, and examined its effect on synapses in vitro and in vivo. Electrophysiological and morphological studies revealed that the neuroligin-3 R704C mutation did not significantly alter synapse formation, but dramatically impaired synapse function. Specifically, the R704C mutation caused a major and selective decrease in AMPA receptor-mediated synaptic transmission in pyramidal neurons of the hippocampus, without similarly changing NMDA or GABA receptor-mediated synaptic transmission, and without detectably altering presynaptic neurotransmitter release. Our results suggest that the cytoplasmic tail of neuroligin-3 has a central role in synaptic transmission by modulating the recruitment of AMPA receptors to postsynaptic sites at excitatory synapses.
ESTHER : Etherton_2011_EMBO.J_30_2908
PubMedSearch : Etherton_2011_EMBO.J_30_2908
PubMedID: 21642956

Title : Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function - Etherton_2011_Proc.Natl.Acad.Sci.U.S.A_108_13764
Author(s) : Etherton M , Foldy C , Sharma M , Tabuchi K , Liu X , Shamloo M , Malenka RC , Sudhof TC
Ref : Proc Natl Acad Sci U S A , 108 :13764 , 2011
Abstract : Multiple independent mutations in neuroligin genes were identified in patients with familial autism, including the R451C substitution in neuroligin-3 (NL3). Previous studies showed that NL3(R451C) knock-in mice exhibited modestly impaired social behaviors, enhanced water maze learning abilities, and increased synaptic inhibition in the somatosensory cortex, and they suggested that the behavioral changes in these mice may be caused by a general shift of synaptic transmission to inhibition. Here, we confirm that NL3(R451C) mutant mice behaviorally exhibit social interaction deficits and electrophysiologically display increased synaptic inhibition in the somatosensory cortex. Unexpectedly, however, we find that the NL3(R451C) mutation produced a strikingly different phenotype in the hippocampus. Specifically, in the hippocampal CA1 region, the NL3(R451C) mutation caused an approximately 1.5-fold increase in AMPA receptor-mediated excitatory synaptic transmission, dramatically altered the kinetics of NMDA receptor-mediated synaptic responses, induced an approximately twofold up-regulation of NMDA receptors containing NR2B subunits, and enhanced long-term potentiation almost twofold. NL3 KO mice did not exhibit any of these changes. Quantitative light microscopy and EM revealed that the NL3(R451C) mutation increased dendritic branching and altered the structure of synapses in the stratum radiatum of the hippocampus. Thus, in NL3(R451C) mutant mice, a single point mutation in a synaptic cell adhesion molecule causes context-dependent changes in synaptic transmission; these changes are consistent with the broad impact of this mutation on murine and human behaviors, suggesting that NL3 controls excitatory and inhibitory synapse properties in a region- and circuit-specific manner.
ESTHER : Etherton_2011_Proc.Natl.Acad.Sci.U.S.A_108_13764
PubMedSearch : Etherton_2011_Proc.Natl.Acad.Sci.U.S.A_108_13764
PubMedID: 21808020
Gene_locus related to this paper: human-NLGN3

Title : Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior - Blundell_2010_J.Neurosci_30_2115
Author(s) : Blundell J , Blaiss CA , Etherton MR , Espinosa F , Tabuchi K , Walz C , Bolliger MF , Sudhof TC , Powell CM
Ref : Journal of Neuroscience , 30 :2115 , 2010
Abstract : Neuroligins (NLs) are a family of neural cell-adhesion molecules that are involved in excitatory/inhibitory synapse specification. Multiple members of the NL family (including NL1) and their binding partners have been linked to cases of human autism and mental retardation. We have now characterized NL1-deficient mice in autism- and mental retardation-relevant behavioral tasks. NL1 knock-out (KO) mice display deficits in spatial learning and memory that correlate with impaired hippocampal long-term potentiation. In addition, NL1 KO mice exhibit a dramatic increase in repetitive, stereotyped grooming behavior, a potential autism-relevant abnormality. This repetitive grooming abnormality in NL1 KO mice is associated with a reduced NMDA/AMPA ratio at corticostriatal synapses. Interestingly, we further demonstrate that the increased repetitive grooming phenotype can be rescued in adult mice by administration of the NMDA receptor partial coagonist d-cycloserine. Broadly, these data are consistent with a role of synaptic cell-adhesion molecules in general, and NL1 in particular, in autism and implicate reduced excitatory synaptic transmission as a potential mechanism and treatment target for repetitive behavioral abnormalities.
ESTHER : Blundell_2010_J.Neurosci_30_2115
PubMedSearch : Blundell_2010_J.Neurosci_30_2115
PubMedID: 20147539

Title : Increased anxiety-like behavior in mice lacking the inhibitory synapse cell adhesion molecule neuroligin 2 - Blundell_2009_Genes.Brain.Behav_8_114
Author(s) : Blundell J , Tabuchi K , Bolliger MF , Blaiss CA , Brose N , Liu X , Sudhof TC , Powell CM
Ref : Genes Brain Behav , 8 :114 , 2009
Abstract : Neuroligins (NL) are postsynaptic cell adhesion molecules that are thought to specify synapse properties. Previous studies showed that mutant mice carrying an autism-associated point mutation in NL3 exhibit social interaction deficits, enhanced inhibitory synaptic function and increased staining of inhibitory synaptic puncta without changes in overall inhibitory synapse numbers. In contrast, mutant mice lacking NL2 displayed decreased inhibitory synaptic function. These studies raised two relevant questions. First, does NL2 deletion impair inhibitory synaptic function by altering the number of inhibitory synapses, or by changing their efficacy? Second, does this effect of NL2 deletion on inhibition produce behavioral changes? We now show that although NL2-deficient mice exhibit an apparent decrease in number of inhibitory synaptic puncta, the number of symmetric synapses as determined by electron microscopy is unaltered, suggesting that NL2 deletion impairs the function of inhibitory synapses without decreasing their numbers. This decrease in inhibitory synaptic function in NL2-deficient mice correlates with a discrete behavioral phenotype that includes a marked increase in anxiety-like behavior, a decrease in pain sensitivity and a slight decrease in motor co-ordination. This work confirms that NL2 modulates inhibitory synaptic function and is the first demonstration that global deletion of NL2 can lead to a selective behavioral phenotype.
ESTHER : Blundell_2009_Genes.Brain.Behav_8_114
PubMedSearch : Blundell_2009_Genes.Brain.Behav_8_114
PubMedID: 19016888

Title : A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice - Tabuchi_2007_Science_318_71
Author(s) : Tabuchi K , Blundell J , Etherton MR , Hammer RE , Liu X , Powell CM , Sudhof TC
Ref : Science , 318 :71 , 2007
Abstract : Autism spectrum disorders (ASDs) are characterized by impairments in social behaviors that are sometimes coupled to specialized cognitive abilities. A small percentage of ASD patients carry mutations in genes encoding neuroligins, which are postsynaptic cell-adhesion molecules. We introduced one of these mutations into mice: the Arg451-->Cys451 (R451C) substitution in neuroligin-3. R451C mutant mice showed impaired social interactions but enhanced spatial learning abilities. Unexpectedly, these behavioral changes were accompanied by an increase in inhibitory synaptic transmission with no apparent effect on excitatory synapses. Deletion of neuroligin-3, in contrast, did not cause such changes, indicating that the R451C substitution represents a gain-of-function mutation. These data suggest that increased inhibitory synaptic transmission may contribute to human ASDs and that the R451C knockin mice may be a useful model for studying autism-related behaviors.
ESTHER : Tabuchi_2007_Science_318_71
PubMedSearch : Tabuchi_2007_Science_318_71
PubMedID: 17823315
Gene_locus related to this paper: human-NLGN3 , human-NLGN4X