Functional characterization of collybistin and gephyrin, key proteins involved in the development of inhibitory synapses

Abstract

Collybistin and gephyrin are key proteins implicated in inhibitory synapse developmentand plasticity that cluster and localize inhibitory neurotransmitter receptors to the neural post synaptic membrane. We have recently reported that collybistin and gephyrin interact with a protein complex that controls translation initiation in eukaryotic cells (eIF3 complex), suggesting that these proteins may also act as regulators of protein synthesis in neurons. However, this novel collybistin and gephyrin function must be confirmed in further studies. One of the aims of this research project is to verify if collybistin and gephyrin are indeed involved in thecontrol of translation initiation. In addition, we have recently started studying a Brazilian patient with a deletion of the entire collybistin gene (ARHGEF9, Xq11.2) who show severe mental retardation, epilepsy, and autistic behavior. In an attempt to explore pathophysiological mechanisms relevant for the development of the neurological impairment in this patient, which may also increase susceptibility to autism, this project also aims to verify if neural cells derived from induced pluripotent stem cells of this patient show morphological, functional and molecular changes (including alterations in protein synthesis). Finally, since this patient has autism and collybistin seems to be involved in biological pathways previously associated with this disease, another aim of the present project is to estimate the contribution of ARHGEF9 mutations to the genetic aetiology of autism. By reaching these three main objectives, this project intends to get a better understanding of collybistin and gephyrin functions, and of biological mechanisms underlying autism, which may allow the development of new and more effective treatments. (AU)