Complex regulation of Gephyrin splicing is a determinant of inhibitory postsynaptic diversity

Abstract

Gephyrin (GPHN) regulates the clustering of postsynaptic components at inhibitory synapses and is involved in pathophysiology of neuropsychiatric disorders. Here, we uncover an extensive diversity of GPHN transcripts that are tightly controlled by splicing during mouse and human brain development. Proteomic analysis reveals at least a hundred isoforms of GPHN incorporated at inhibitory Glycine and GABA-A receptors containing synapses. They exhibit different localization and postsynaptic clustering properties, and altering the expression level of one isoform is sufficient to affect the number, size, and density of inhibitory synapses in cerebellar Purkinje cells. Furthermore, we discovered that splicing defects reported in neuropsychiatric disorders are carried by multiple alternative GPHN transcripts, demonstrating the need for a thorough analysis of the GPHN transcriptome in patients. Overall, we show that alternative splicing of GPHN is an important genetic variation to consider in neurological diseases and a determinant of the diversity of postsynaptic inhibitory synapses.

Functional Neuroligin-2-MDGA1 interactions differentially regulate synaptic GABAARs and cytosolic gephyrin aggregation

“…These data lead to the fascinating conclusion that it is this reduction of gephyrin aggregates, rather than the exacerbation of the loss of gephyrin from layer S.R., that dominates the functional consequences of combined deletion of Nlgn2 and MDGA1. While the mechanistic link between the cytoplasmic gephyrin aggregates and the functional consequences at the cellular and behavioral level remains to be established, regional differences in the expression of gephyrin splice forms (51) or the differential recruitment and trafficking of GABA A R subunits other than GABA A Rγ2 may play a role.…”