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 GABA A Rs 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. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.

Defective excitatory/inhibitory synaptic balance and increased neuron apoptosis in a zebrafish model of Dravet syndrome

“…PSD-95 by its PDZ domains serves as a scaffolding protein with a docking site for signaling proteins clustering around NMDA-and AMPA-type glutamate receptors, which are crucial for excitatory neurotransmission and synaptic plasticity [34]. Gephyrin is a core scaffolding protein, the postsynaptic component of inhibitory synapses, and it controls the formation and plasticity of inhibitory synapses through regulation of GABAA and glycine receptors [35]. In the present study, we demonstrated that the levels of PSD-95 and gephyrin are modified in zebrafish models of DS.…”

Defective Excitatory/Inhibitory Synaptic Balance and Increased Neuron Apoptosis in a Zebrafish Model of Dravet Syndrome

“…PSD-95, by its PDZ domains, serves as a scaffolding protein with a docking site for signaling proteins clustering around NMDA- and AMPA- type glutamate receptors, which are crucial for excitatory neurotransmission and synaptic plasticity [34]. Gephyrin is a core scaffolding protein, the postsynaptic component of inhibitory synapses, and it controls the formation and plasticity of inhibitory synapses through regulation of GABAA and glycine receptors [35]. In the present study, we demonstrated that levels of PSD-95 and gephyrin are modified in zebrafish models of DS.…”

Impaired formation of high-order gephyrin oligomers underlies gephyrin dysfunction-associated pathologies

“…Gephyrin contributes to the accumulation of GABA A receptors at postsynaptic sites by interacting with several key GABAergic synapse-specific proteins, enabling efficient inhibitory synaptic transmission ( Betz, 1998 ; Choii and Ko, 2015 ; Fritschy et al., 2008 ; Groeneweg et al., 2018 ; Pizzarelli et al., 2019 ; Tyagarajan and Fritschy, 2014 ). In addition, gephyrin is known to be required for synaptic clustering of glycine receptors (GlyRs) in the spinal cord and for molybdoenzyme activity in non-neuronal tissues ( Feng et al., 1998 ; Kirsch et al., 1993 ; Stallmeyer et al., 1999 ).…”

“…In addition, gephyrin is known to be required for synaptic clustering of glycine receptors (GlyRs) in the spinal cord and for molybdoenzyme activity in non-neuronal tissues ( Feng et al., 1998 ; Kirsch et al., 1993 ; Stallmeyer et al., 1999 ). Gephyrin is composed of three functional domains: an N-terminal G-domain, a central C-domain, and a C-terminal E-domain ( Choii and Ko, 2015 ; Kim et al., 2006 ; Pizzarelli et al., 2019 ; Sola et al., 2004 ). At postsynaptic sites, gephyrin assembles through G- and E-domain–mediated interactions into a complex submembranous lattice that is dynamically regulated by a number of posttranslational modifications and interactions with other binding proteins ( Choii and Ko, 2015 ; Groeneweg et al., 2018 ; Tyagarajan and Fritschy, 2014 ).…”