Conformational state-dependent regulation of GABA_A receptor diffusion and subsynaptic domains

The efficacy of GABAergic synapses relies on the number of postsynaptic GABA_A receptors (GABA_ARs), which is regulated by a diffusion capture mechanism. Here, we report that the conformational state of GABA_ARs influences their membrane dynamics. Indeed, pharmacological and mutational manipulations of receptor favoring active or desensitized states altered GABA_AR diffusion leading to the disorganization of GABA_AR subsynaptic domains and gephyrin scaffold, as detected by super-resolution microscopy. Active and desensitized receptors were confined to perisynaptic endocytic zones, and some of them were further internalized. We propose that following their activation or desensitization, synaptic receptors rapidly diffuse at the periphery of the synapse where they remain confined until they switch back to a resting state or are internalized. We speculate that this allows a renewal of activatable receptors at the synapse, contributing to maintain the efficacy of the synaptic transmission, in particular on sustained GABA transmission.