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标题：Activity-dependent inhibitory synapse remodeling through gephyrin phosphorylation
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作者：Carmen E. Flores ; Irina Nikonenko ; Pablo Mendez 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：1
页码：E65-E72
DOI：10.1073/pnas.1411170112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceLearning mechanisms rely on plasticity properties of excitatory synapses and an activity-dependent rewiring of excitatory networks. Inhibitory synapses also display plasticity properties, but it remains unknown whether and how excitatory activity and plasticity can affect the organization of inhibitory networks. Here we show that synaptic and neuronal activity directly regulates the number and function of perisomatic inhibitory synapses through a mechanism that involves the phosphorylation of gephyrin by the enzyme calcium/calmodulin-dependent protein kinase II. The results identify a homeostatic mechanism through which cell activity can continuously adjust its excitation/inhibition balance. 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 Ca2+/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.
关键词：inhibition ; gabaergic synapse ; plasticity ; hippocampus ; CaMKII