<scp>GABA_A</scp> receptors and plasticity of inhibitory neurotransmission in the central nervous system

<jats:title>Abstract</jats:title><jats:p><jats:styled-content style="fixed-case">GABA<jats:sub>A</jats:sub></jats:styled-content> receptors (<jats:styled-content style="fixed-case">GABA<jats:sub>A</jats:sub>R</jats:styled-content>s) are ligand‐gated Cl<jats:sup>−</jats:sup> channels that mediate most of the fast inhibitory neurotransmission in the central nervous system (<jats:styled-content style="fixed-case">CNS</jats:styled-content>). Multiple <jats:styled-content style="fixed-case">GABA<jats:sub>A</jats:sub>R</jats:styled-content> subtypes are assembled from a family of 19 subunit genes, raising the question of the significance of this heterogeneity. In this review, we discuss the evidence that <jats:styled-content style="fixed-case">GABA<jats:sub>A</jats:sub>R</jats:styled-content> subtypes represent distinct receptor populations with a specific spatio‐temporal expression pattern in the developing and adult <jats:styled-content style="fixed-case">CNS</jats:styled-content>, being endowed with unique functional and pharmacological properties, as well as being differentially regulated at the transcriptional, post‐transcriptional and translational levels. <jats:styled-content style="fixed-case">GABA<jats:sub>A</jats:sub>R</jats:styled-content> subtypes are targeted to specific subcellular domains to mediate either synaptic or extrasynaptic transmission, and their action is dynamically regulated by a vast array of molecular mechanisms to adjust the strength of inhibition to the changing needs of neuronal networks. These adaptations involve not only changing the gating or kinetic properties of <jats:styled-content style="fixed-case">GABA<jats:sub>A</jats:sub>R</jats:styled-content>s, but also modifying the postsynaptic scaffold organised by gephyrin to anchor specific receptor subtypes at postsynaptic sites. The significance of <jats:styled-content style="fixed-case">GABA<jats:sub>A</jats:sub>R</jats:styled-content> heterogeneity is particularly evident during <jats:styled-content style="fixed-case">CNS</jats:styled-content> development and adult neurogenesis, with different receptor subtypes fulfilling distinct steps of neuronal differentiation and maturation. Finally, analysis of the specific roles of <jats:styled-content style="fixed-case">GABA<jats:sub>A</jats:sub>R</jats:styled-content> subtypes reveals their involvement in the pathophysiology of major <jats:styled-content style="fixed-case">CNS</jats:styled-content> disorders, and opens novel perspectives for therapeutic intervention. In conclusion, <jats:styled-content style="fixed-case">GABA<jats:sub>A</jats:sub>R</jats:styled-content> subtypes represent the substrate of a multifaceted inhibitory neurotransmission system that is dynamically regulated and performs multiple operations, contributing globally to the proper development, function and plasticity of the <jats:styled-content style="fixed-case">CNS</jats:styled-content>.</jats:p>