GABAA receptors and plasticity of inhibitory neurotransmission in the central nervous system

    loading  Checking for direct PDF access through Ovid


GABAA receptors (GABAARs) are ligand-gated Cl− channels that mediate most of the fast inhibitory neurotransmission in the central nervous system (CNS). Multiple GABAAR 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 GABAAR subtypes represent distinct receptor populations with a specific spatio-temporal expression pattern in the developing and adult CNS, being endowed with unique functional and pharmacological properties, as well as being differentially regulated at the transcriptional, post-transcriptional and translational levels. GABAAR 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 GABAARs, but also modifying the postsynaptic scaffold organised by gephyrin to anchor specific receptor subtypes at postsynaptic sites. The significance of GABAAR heterogeneity is particularly evident during CNS development and adult neurogenesis, with different receptor subtypes fulfilling distinct steps of neuronal differentiation and maturation. Finally, analysis of the specific roles of GABAAR subtypes reveals their involvement in the pathophysiology of major CNS disorders, and opens novel perspectives for therapeutic intervention. In conclusion, GABAAR 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 CNS.

GABAA receptor heterogeneity arises through combinatorial assembly of a large family of subunits to generate multiple receptor subtypes. It is an important facet of the variety of GABAergic signaling in adult and developing CNS, and a key factor underlying GABAergic synaptic plasticity underlying excitatory/inhibitory balance in neuronal circuits. This review presents and discusses recent progress in elucidating the relevance of GABAA receptor heterogeneity for CNS function in health and disease.

Related Topics

    loading  Loading Related Articles