Abstract
Inhibitory synapse diversity is supported by multiple classes of interneurons with distinct morphologies, connectivity patterns and physiological properties. Yet, the specific molecular determinants of inhibitory synapse diversity remain largely unknown. We studied gephyrin (Gphn), which is considered the major scaffolding protein of inhibitory synapses that controls the localization and function of inhibitory receptors, but is also responsible for the organization of the different actors of the inhibitory postsynapse. Previous studies have revealed that gephyrin is subject to alternative splicing, although a limited amount of variants had been identified, and that the expression of aberrant splicing variants of GPHN has been identified as a risk factor for different neurological disorders, such as schizophrenia, autism, or epilepsy. In the course of this study, we have discovered 277 splice variants of Gphn expressed during brain development, generating a complex Gphn proteome, visibly regulated depending on the localization but also on the developmental stage. Our immunohistochemistry studies revealed distinct localization but also clustering properties between the different variants. Our in vivo data showed how changes in Gphn isoform expression control the formation of inhibitory synapses in the cerebellar cortex, demonstrating that the complexity of isoforms of a single postsynaptic scaffolding protein contributes to the molecular diversity of inhibitory synapses in the brain.