title: Regulation of GABAergic synapse formation and plasticity by GSK3beta-dependent phosphorylation of gephyrin.
abstract: Postsynaptic scaffolding proteins ensure efficient neurotransmission by anchoring receptors and signaling molecules in synapse-specific subcellular domains. In turn, posttranslational modifications of scaffolding proteins contribute to synaptic plasticity by remodeling the postsynaptic apparatus. Though these mechanisms are operant in glutamatergic synapses, little is known about regulation of GABAergic synapses, which mediate inhibitory transmission in the CNS. Here, we focused on gephyrin, the main scaffolding protein of GABAergic synapses. We identify a unique phosphorylation site in gephyrin, Ser270, targeted by glycogen synthase kinase 3β (GSK3β) to modulate GABAergic transmission. Abolishing Ser270 phosphorylation increased the density of gephyrin clusters and the frequency of miniature GABAergic postsynaptic currents in cultured hippocampal neurons. Enhanced, phosphorylation-dependent gephyrin clustering was also induced in vitro and in vivo with lithium chloride. Lithium is a GSK3β inhibitor used therapeutically as mood-stabilizing drug, which underscores the relevance of this posttranslational modification for synaptic plasticity. Conversely, we show that gephyrin availability for postsynaptic clustering is limited by Ca(2+)-dependent gephyrin cleavage by the cysteine protease calpain-1. Together, these findings identify gephyrin as synaptogenic molecule regulating GABAergic synaptic plasticity, likely contributing to the therapeutic action of lithium.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich, Switzerland. tyagarajan@pharma.uzh.ch
authors.forename: Shiva K
authors.initials: SK
authors.lastname: Tyagarajan
authors.forename: Himanish
authors.initials: H
authors.lastname: Ghosh
authors.forename: Gonzalo E
authors.initials: GE
authors.lastname: Yévenes
authors.forename: Irina
authors.initials: I
authors.lastname: Nikonenko
authors.forename: Claire
authors.initials: C
authors.lastname: Ebeling
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schwerdel
authors.forename: Corinne
authors.initials: C
authors.lastname: Sidler
authors.forename: Hanns Ulrich
authors.initials: HU
authors.lastname: Zeilhofer
authors.forename: Bertran
authors.initials: B
authors.lastname: Gerrits
authors.forename: Dominique
authors.initials: D
authors.lastname: Muller
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Fritschy
mesh_terms: D000818:Animals; D002154:Calpain / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004594:Electrophysiology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology*; D007150:Immunohistochemistry; D018021:Lithium Chloride / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D013569:Synapses / Q000502:physiology*; D053719:Tandem Mass Spectrometry
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C073441:gephyrin; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D002154:Calpain; D018021:Lithium Chloride