Earlier studies delineated the precise arrangement of proteins that drive neurotransmitter release and postsynaptic signaling at excitatory synapses. However, spatial organization of neurotransmission at inhibitory synapses remains unclear. Here, we took advantage of the molecularly specific interaction of antimalarial Artemisinins, and inhibitory synapse scaffold protein, gephyrin, to probe the functional organization of gamma-aminobutyric acid A receptor (GABAaR)-mediated neurotransmission in central synapses. Short-term application of Artemisinins severely contracted the size and density of gephyrin and GABAaR γ2 subunit clusters. This size contraction elicited a neuronal activity-independent increase in Bdnf expression due to a specific reduction in GABAergic spontaneous, but not evoked, neurotransmission. The same functional effect could be mimicked by disruption of microtubules that link gephyrin to the neuronal cytoskeleton. These results suggest the GABAergic postsynaptic apparatus possesses a concentric center-surround organization, where the periphery of gephyrin clusters selectively maintain spontaneous GABAergic neurotransmission facilitating its autonomous function regulating Bdnf expression.
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Ege Kavalali, Ph.D., Professor & Chair, Department of Pharmacology, Vanderbilt School of Medicine
Natalie Guzikowski, Ph.D. Neuroscience Student, Vanderbilt University and member of the Kavalali Lab