Petrini Enrica Maria, Ravasenga Tiziana, Hausrat Torben J, Iurilli Giuliano, Olcese Umberto, Racine Victor, Sibarita Jean-Baptiste, Jacob Tija C, Moss Stephen J, Benfenati Fabio, Medini Paolo, Kneussel Matthias, Barberis Andrea
Department of Neuroscience and Brain Technologies, The Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy.
Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg Eppendorf, D-20251 Hamburg, Germany.
Nat Commun. 2014 Jun 4;5:3921. doi: 10.1038/ncomms4921.
Postsynaptic long-term potentiation of inhibition (iLTP) can rely on increased GABAA receptors (GABA(A)Rs) at synapses by promoted exocytosis. However, the molecular mechanisms that enhance the clustering of postsynaptic GABA(A)Rs during iLTP remain obscure. Here we demonstrate that during chemically induced iLTP (chem-iLTP), GABA(A)Rs are immobilized and confined at synapses, as revealed by single-particle tracking of individual GABA(A)Rs in cultured hippocampal neurons. Chem-iLTP expression requires synaptic recruitment of the scaffold protein gephyrin from extrasynaptic areas, which in turn is promoted by CaMKII-dependent phosphorylation of GABA(A)R-β3-Ser(383). Impairment of gephyrin assembly prevents chem-iLTP and, in parallel, blocks the accumulation and immobilization of GABA(A)Rs at synapses. Importantly, an increase of gephyrin and GABA(A)R similar to those observed during chem-iLTP in cultures were found in the rat visual cortex following an experience-dependent plasticity protocol that potentiates inhibitory transmission in vivo. Thus, phospho-GABA(A)R-β3-dependent accumulation of gephyrin at synapses and receptor immobilization are crucial for iLTP expression and are likely to modulate network excitability.
突触后抑制性长时程增强（iLTP）可通过促进胞吐作用增加突触处的γ-氨基丁酸A型受体（GABAARs）来实现。然而，iLTP过程中增强突触后GABAARs聚集的分子机制仍不清楚。在此，我们证明在化学诱导的iLTP（化学性iLTP，chem-iLTP）过程中，GABAARs被固定并局限于突触处，这是通过对培养的海马神经元中单个GABAARs进行单颗粒追踪所揭示的。化学性iLTP的表达需要从突触外区域招募支架蛋白gephyrin至突触，而这又由CaMKII依赖的GABAAR-β3-Ser(383)磷酸化所促进。gephyrin组装的受损会阻止化学性iLTP，并同时阻断GABAARs在突触处的积累和固定。重要的是，在经历了增强体内抑制性传递的经验依赖性可塑性方案后，在大鼠视皮层中发现了与在培养物中化学性iLTP期间观察到的类似的gephyrin和GABAAR增加。因此，磷酸化GABAAR-β3依赖的gephyrin在突触处的积累和受体固定对于iLTP的表达至关重要，并且可能调节网络兴奋性。
