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The α3 subunit of GABA_A receptors promotes formation of inhibitory synapses in the absence of collybistin.

ABSTRACT: Signaling at nerve cell synapses is a key determinant of proper brain function, and synaptic defects-or synaptopathies-are at the basis of many neurological and psychiatric disorders. Collybistin (CB), a brain-specific guanine nucleotide exchange factor, is essential for the formation of γ-aminobutyric acidergic (GABAergic) postsynapses in defined regions of the mammalian forebrain, including the hippocampus and basolateral amygdala. This process depends on a direct interaction of CB with the scaffolding protein gephyrin, which leads to the redistribution of gephyrin into submembranous clusters at nascent inhibitory synapses. Strikingly, synaptic clustering of gephyrin and GABA_A type A receptors (GABA_ARs) in several brain regions, including the cerebral cortex and certain thalamic areas, is unperturbed in CB-deficient mice, indicating that the formation of a substantial subset of inhibitory postsynapses must be controlled by gephyrin-interacting proteins other than CB. Previous studies indicated that the α3 subunit of GABA_ARs (GABA_AR-α3) binds directly and with high affinity to gephyrin. Here, we provide evidence (i) that a homooligomeric GABA_AR-α3^A343W mutant induces the formation of submembranous gephyrin clusters independently of CB in COS-7 cells, (ii) that gephyrin clustering is unaltered in the neuronal subpopulations endogenously expressing the GABA_AR-α3 in CB-deficient brains, and (iii) that exogenous expression of GABA_AR-α3 partially rescues impaired gephyrin clustering in CB-deficient hippocampal neurons. Our results identify an important role of GABA_AR-α3 in promoting gephyrin-mediated and CB-independent formation of inhibitory postsynapses.

SUBMITTER: Wagner S

PROVIDER: S-EPMC8141935 | biostudies-literature |

REPOSITORIES: biostudies-literature

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