Collybistin is required for both the formation and maintenance of GABAergic postsynapses in the hippocampus

Papadopoulos, Theofilos; Eulenburg, Volker; Reddy-Alla, Suneel; Mansuy, Isabelle M.; Li, Yu Qing; Betz, Heinrich

doi:10.1016/j.mcn.2008.06.006

Cited by 70 publications

(84 citation statements)

References 35 publications

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“…For instance, α1-GABA A Rs are retained in Purkinje cells of CB-KO mice in the absence of gephyrin [54], suggesting their synaptic anchoring via the DGC and NL2. In contrast, in CA1 pyramidal cells, gephyrin, α1-and α2-GABA A R disappear in CB-KO mice, whereas in PV + interneurons (and in thalamic VB neurons), gephyrin and α1-GABA A R are retained [77]. However, since the α2-subunit interacts directly with CB2 [48], one might hypothesize that GABAergic synapses containing α2-GABA A R are selectively affected in CB-KO mice.…”

Section: Model Of Psd Protein Clustering At Gabaergic Synapsesmentioning

confidence: 95%

“…In particular, in GABAergic synapses of the forebrain and cerebellum, multiple phenotypes were observed in CB-KO mice, ranging from disruption of both gephyrin and GABA A R clusters (e.g., CA1 pyramidal cells) to complete preservation of these clusters (e.g., PV + interneurons in CA1), passing by partial alteration (loss of gephyrin, but not GABA A R, clusters in Purkinje cells of the cerebellum) [54,77]. Although preservation of gephyrin clusters might point to a functional homologue of CB, the phenotype of Purkinje cells rather indicates that clustering of gephyrin and of GABA A R depends on different mechanisms, with only the former requiring the presence of CB.…”

Section: Heterogeneity Of Gabaergic Synapses Revealed In Mice With Tamentioning

confidence: 99%

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Molecular and functional heterogeneity of GABAergic synapses

Fritschy

Panzanelli

Tyagarajan

2012

Cell. Mol. Life Sci.

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Knowledge of the functional organization of the GABAergic system, the main inhibitory neurotransmitter system, in the CNS has increased remarkably in recent years. In particular, substantial progress has been made in elucidating the molecular mechanisms underlying the formation and plasticity of GABAergic synapses. Evidence available ascribes a key role to the cytoplasmic protein gephyrin to form a postsynaptic scaffold anchoring GABA(A) receptors along with other transmembrane proteins and signaling molecules in the postsynaptic density. However, the mechanisms of gephyrin scaffolding remain elusive, notably because gephyrin can auto-aggregate spontaneously and lacks PDZ protein interaction domains found in a majority of scaffolding proteins. In addition, the structural diversity of GABA(A) receptors, which are pentameric channels encoded by a large family of subunits, has been largely overlooked in these studies. Finally, the role of the dystrophin-glycoprotein complex, present in a subset of GABAergic synapses in cortical structures, remains ill-defined. In this review, we discuss recent results derived mainly from the analysis of mutant mice lacking a specific GABA(A) receptor subtype or a core protein of the GABAergic postsynaptic density (neuroligin-2, collybistin), highlighting the molecular diversity of GABAergic synapses and its relevance for brain plasticity and function. In addition, we discuss the contribution of the dystrophin-glycoprotein complex to the molecular and functional heterogeneity of GABAergic synapses. AbstractKnowledge of the functional organization of the GABAergic system, the main inhibitory neurotransmitter system, in the CNS has increased remarkably in recent years. In particular, substantial progress has been made in elucidating the molecular mechanisms underlying formation and plasticity of GABAergic synapses. Evidence available ascribes a key role to the cytoplasmic protein gephyrin to form a postsynaptic scaffold anchoring GABA A receptors along with other transmembrane proteins and signaling molecules in the postsynaptic density. However, the mechanisms of gephyrin scaffolding remain elusive, notably because gephyrin can auto-aggregate spontaneously and lacks PDZ protein interaction domains found in a majority of scaffolding proteins. In addition, the structural diversity of GABA A receptors, which are pentameric channels encoded by a large family of subunits, has been largely overlooked in these studies. Finally, the role of the dystrophin-glycoprotein complex, present in a subset of GABAergic synapses in cortical structures, remains ill-defined. In this review, we discuss recent results derived mainly from the analysis of mutant mice lacking a specific GABA A receptor subtype or a core protein of the GABAergic postsynaptic density (neuroligin-2, collybistin), highlighting the molecular diversity of GABAergic synapses and its relevance for brain plasticity and function. In addition, we discuss the contribution of the dystrophinglycoprotein complex to the molecular ...

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Section: Model Of Psd Protein Clustering At Gabaergic Synapsesmentioning

confidence: 95%

Section: Heterogeneity Of Gabaergic Synapses Revealed In Mice With Tamentioning

confidence: 99%

Molecular and functional heterogeneity of GABAergic synapses

Fritschy

Panzanelli

Tyagarajan

2012

Cell. Mol. Life Sci.

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“…79 Similar functional alterations were reproduced in conditional collybistin-knockout mice. 80 Moreover, increased granule cell excitability, somatic GABAergic network inhibition and impaired induction of LTP in the dentate gyrus of the Figure 2 Architecture of gephyrin-containing complexes at inhibitory synapses: the structure of an inhibitory synapse focusing on gephyrin and its interactors at the synaptic membrane and intracellular compartments. Gephyrin (drawn as blue hexagonal lattices beneath the postsynaptic membrane) acts as a hub for inhibitory signal-transduction pathways through GABA A receptors, GlyRs and neuroligin-2, and binds to other proteins through its modular structure (see Figure 1 for the domain structure of gephyrin).…”

Section: Collybistinmentioning

confidence: 99%

Gephyrin: a central GABAergic synapse organizer

2015

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Gephyrin is a central element that anchors, clusters and stabilizes glycine and γ-aminobutyric acid type A receptors at inhibitory synapses of the mammalian brain. It self-assembles into a hexagonal lattice and interacts with various inhibitory synaptic proteins. Intriguingly, the clustering of gephyrin, which is regulated by multiple posttranslational modifications, is critical for inhibitory synapse formation and function. In this review, we summarize the basic properties of gephyrin and describe recent findings regarding its roles in inhibitory synapse formation, function and plasticity. We will also discuss the implications for the pathophysiology of brain disorders and raise the remaining open questions in this field.

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“…16 Previously, some other ARHGEF9 mutations have been reported. The first reported missense mutation, p.G55A in the SH3 domain, was found in a male patient with severe mental retardation, hyperekplexia, drug-resistant seizures and premature death.…”

Section: Loss-of-function Mutation Of Collybistin K Shimojima Et Almentioning

confidence: 99%