title: Activity-dependent inhibitory synapse remodeling through gephyrin phosphorylation.
abstract: Maintaining a proper balance between excitation and inhibition is essential for the functioning of neuronal networks. However, little is known about the mechanisms through which excitatory activity can affect inhibitory synapse plasticity. Here we used tagged gephyrin, one of the main scaffolding proteins of the postsynaptic density at GABAergic synapses, to monitor the activity-dependent adaptation of perisomatic inhibitory synapses over prolonged periods of time in hippocampal slice cultures. We find that learning-related activity patterns known to induce N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation and transient optogenetic activation of single neurons induce within hours a robust increase in the formation and size of gephyrin-tagged clusters at inhibitory synapses identified by correlated confocal electron microscopy. This inhibitory morphological plasticity was associated with an increase in spontaneous inhibitory activity but did not require activation of GABAA receptors. Importantly, this activity-dependent inhibitory plasticity was prevented by pharmacological blockade of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), it was associated with an increased phosphorylation of gephyrin on a site targeted by CaMKII, and could be prevented or mimicked by gephyrin phospho-mutants for this site. These results reveal a homeostatic mechanism through which activity regulates the dynamics and function of perisomatic inhibitory synapses, and they identify a CaMKII-dependent phosphorylation site on gephyrin as critically important for this process.
authors.affiliation: Département des Neurosciences Fondamentales, Faculté de Médecine, Centre Médical Universitaire, Université de Genève, 1211 Geneve 4, Switzerland; and.
authors.forename: Carmen E
authors.initials: CE
authors.lastname: Flores
authors.affiliation: Département des Neurosciences Fondamentales, Faculté de Médecine, Centre Médical Universitaire, Université de Genève, 1211 Geneve 4, Switzerland; and.
authors.forename: Irina
authors.initials: I
authors.lastname: Nikonenko
authors.affiliation: Département des Neurosciences Fondamentales, Faculté de Médecine, Centre Médical Universitaire, Université de Genève, 1211 Geneve 4, Switzerland; and.
authors.forename: Pablo
authors.initials: P
authors.lastname: Mendez
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich, 8057 Zurich, Switzerland.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Fritschy
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich, 8057 Zurich, Switzerland.
authors.forename: Shiva K
authors.initials: SK
authors.lastname: Tyagarajan
authors.affiliation: Département des Neurosciences Fondamentales, Faculté de Médecine, Centre Médical Universitaire, Université de Genève, 1211 Geneve 4, Switzerland; and dominique.muller@unige.ch.
authors.forename: Dominique
authors.initials: D
authors.lastname: Muller
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism* / Q000648:ultrastructure; D006624:Hippocampus / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D009433:Neural Inhibition / Q000187:drug effects; D062308:Optogenetics; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D011724:Pyridazines; D011963:Receptors, GABA-A; C073441:gephyrin; C049853:gabazine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: CaMKII; gabaergic synapse; hippocampus; inhibition; plasticity