Tuning GABAergic Inhibition: Gephyrin Molecular Organization and Functions

Abstract

To be highly reliable, synaptic transmission needs postsynaptic receptors (Rs) in
precise apposition to the presynaptic release sites. At inhibitory synapses, the 
postsynaptic protein gephyrin self-assembles to form a scaffold that anchors
glycine and GABAARs to the cytoskeleton, thus ensuring the accurate accumulation 
of postsynaptic receptors at the right place. This protein undergoes several
post-translational modifications which control protein-protein interaction and
downstream signaling pathways. In addition, through the constant exchange of
scaffolding elements and receptors in and out of synapses, gephyrin dynamically
regulates synaptic strength and plasticity. The aim of the present review is to
highlight recent findings on the functional role of gephyrin at GABAergic
inhibitory synapses. We will discuss different approaches used to interfere with 
gephyrin in order to unveil its function. In addition, we will focus on the
impact of gephyrin structure and distribution at the nanoscale level on the
functional properties of inhibitory synapses as well as the implications of this 
scaffold protein in synaptic plasticity processes. Finally, we will emphasize how
gephyrin genetic mutations or alterations in protein expression levels are
implicated in several neuropathological disorders, including autism spectrum
disorders, schizophrenia, temporal lobe epilepsy and Alzheimer's disease, all
associated with severe deficits of GABAergic signaling.