GephyrinΔ199-233 - an epileptogenic microdeletion

Abstract Gephyrin, as the main organizer of inhibitory synapses, is crucial for inhibitory signal transmission, and implicated in various neurological disorders. Various studies have identified gephyrin microdeletions in conditions of autism, schizophrenia, and epilepsy. Those deletions affected the N-terminal G-domain and/or the central C-domain of gephyrin while the receptor binding C-terminal E-domain was not affected. Here, we investigated the importance of a specific microdeletion (Δ199-233) within the C-domain using a full-body knock-in mouse model. Homozygous mice displayed a severe phenotype characterized by reduced fertility, increased mortality, and neurological deficits at early developmental stages. Analyses in dissociated hippocampal neurons demonstrated disrupted synaptic targeting of gephyrin Δ199-233 that harbors the functionally important S-palmitoylation site at Cys212. Simultaneously, we found adaptations at the excitatory synapse, with smaller, but more numerous clusters of the excitatory scaffolding protein PSD95. Although, gephyrin Δ199-233 showed unexpectedly a facilitated receptor interaction, inhibitory signal transmission was reduced. We hypothesize, that the gephyrin Δ199-233-mediated reduction of inhibition triggers compensatory excitation, which possibly fails and/or disrupts the excitation/inhibition ratio in our mouse model. These findings highlight the critical role of the gephyrin C-domain and its post-translational modifications in synaptic function and neuronal health, offering a novel mouse model for the development of potential therapeutic targets addressing gephyrin-associated neurological disorders.