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Regulation of GABAergic synapse formation and plasticity by GSK3beta-dependent phosphorylation of gephyrin

Tyagarajan, Shiva K
Ghosh, Himanish
Yévenes, Gonzalo E
Ebeling, Claire
Schwerdel, Cornelia
Sidler, Corinne
Zeilhofer, Hanns Ulrich
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Published in Proceedings of the National Academy of Sciences. 2011, vol. 108, no. 1, p. 379-84
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.
Keywords AnimalsCalpain/metabolismCarrier Proteins/metabolismCells, CulturedElectrophysiologyGlycogen Synthase Kinase 3/antagonists & inhibitors/metabolismHippocampus/cytologyImmunohistochemistryLithium Chloride/pharmacologyMembrane Proteins/metabolismNeuronal Plasticity/physiologyNeurons/metabolism/physiologyPhosphorylationRatsSynapses/physiologyTandem Mass Spectrometry
PMID: 21173228
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Research group Plasticité des synapses excitatrices (76)
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TYAGARAJAN, Shiva K et al. Regulation of GABAergic synapse formation and plasticity by GSK3beta-dependent phosphorylation of gephyrin. In: Proceedings of the National Academy of Sciences, 2011, vol. 108, n° 1, p. 379-84. doi: 10.1073/pnas.1011824108 https://archive-ouverte.unige.ch/unige:25245

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Deposited on : 2013-01-09

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