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

Neuropharmacology
Megan L BradyTija C Jacob

Abstract

γ-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 d...Continue Reading

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Citations

Jul 13, 2019·Frontiers in Pharmacology·Amanda ThomazRafael Roesler
May 14, 2019·Frontiers in Cellular Neuroscience·Joshua M Lorenz-GuertinTija C Jacob
Sep 14, 2018·Frontiers in Cellular Neuroscience·Christophe PorcherJean-Luc Gaiarsa
Oct 22, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Sadia Zafar, Ishrat Jabeen
Oct 27, 2020·Frontiers in Neuroscience·Hanista PremachandranMaithe Arruda-Carvalho

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