• Neuropharmacology · Jan 2018

    Depolarizing, inhibitory GABA type A receptor activity regulates GABAergic synapse plasticity via ERK and BDNF signaling.

    • Megan L Brady, Jyotsna Pilli, Joshua M Lorenz-Guertin, Sabyasachi Das, Charles E Moon, Nicholas Graff, and Tija C Jacob.
    • Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
    • Neuropharmacology. 2018 Jan 1; 128: 324-339.

    Abstractγ-aminobutyric acid (GABA) begins as the key excitatory neurotransmitter in newly forming circuits, with chloride efflux from GABA type A receptors (GABAARs) producing membrane depolarization, which promotes calcium entry, dendritic outgrowth and synaptogenesis. As development proceeds, GABAergic signaling switches to inhibitory hyperpolarizing neurotransmission. Despite the evidence of impaired GABAergic neurotransmission in neurodevelopmental disorders, little is understood on how agonist-dependent GABAAR activation controls the formation and plasticity of GABAergic synapses. We have identified a weakly depolarizing and inhibitory GABAAR response in cortical neurons that occurs during the transition period from GABAAR depolarizing excitation to hyperpolarizing inhibitory activity. We show here that treatment with the GABAAR agonist muscimol mediates structural changes that diminish GABAergic synapse strength through postsynaptic and presynaptic plasticity via intracellular Ca2+ stores, ERK and BDNF/TrkB signaling. Muscimol decreases synaptic localization of surface γ2 GABAARs and gephyrin postsynaptic scaffold while β2/3 non-γ2 GABAARs accumulate in the synapse. Concurrent with this structural plasticity, muscimol treatment decreases synaptic currents while enhancing the γ2 containing benzodiazepine sensitive GABAAR tonic current in an ERK dependent manner. We further demonstrate that GABAAR activation leads to a decrease in presynaptic GAD65 levels via BDNF/TrkB signaling. Together these data reveal a novel mechanism for agonist induced GABAergic synapse plasticity that can occur on the timescale of minutes, contributing to rapid modification of synaptic and circuit function.Copyright © 2017 Elsevier Ltd. All rights reserved.

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