Release your inhibitions: The cell biology of GABAergic postsynaptic plasticity

Abstract

GABAergic synaptic inhibition controls circuit function by regulating neuronal plasticity, excitability, and firing. To achieve these goals, inhibitory synapses themselves undergo several forms of plasticity via diverse mechanisms, strengthening and weakening phasic inhibition in response to numerous activity-induced stimuli. These mechanisms include changing the number and arrangement of functional GABA_ARs within the inhibitory postsynaptic domain (iPSD), which can profoundly regulate inhibitory synapse strength. Here, we explore recent advances in our molecular understanding of inhibitory postsynaptic plasticity, with a focus on modulation of the trafficking, protein-protein interactions, nanoscale-organization, and posttranscriptional regulation of GABA_ARs and iPSD proteins. What has emerged is a complex mechanistic picture of how synaptic inhibition is controlled, with critical ramifications for cognition under typical and pathogenic conditions.

Keywords: GABA(A) receptor; Gephyrin; Inhibitory synaptic plasticity; Nanoscale organization; Protein synthesis; Receptor trafficking; Synaptic inhibition.