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

Abstract

γ-aminobutyric acid (GABA) begins as the key excitatory neurotransmitter in newly forming circuits, with chloride efflux from GABA type A receptors (GABARs) 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 GABAR activation controls the formation and plasticity of GABAergic synapses. We have identified a weakly depolarizing and inhibitory GABAR response in cortical neurons that occurs during the transition period from GABAR depolarizing excitation to hyperpolarizing inhibitory activity. We show here that treatment with the GABAR agonist muscimol mediates structural changes that diminish GABAergic synapse strength through postsynaptic and presynaptic plasticity via intracellular Ca stores, ERK and BDNF/TrkB signaling. Muscimol decreases synaptic localization of surface γ2 GABARs and gephyrin postsynaptic scaffold while β2/3 non-γ2 GABARs accumulate in the synapse. Concurrent with this structural plasticity, muscimol treatment decreases synaptic currents while enhancing the γ2 containing benzodiazepine sensitive GABAR tonic current in an ERK dependent manner. We further demonstrate that GABAR 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.

Diazepam Accelerates GABAAR Synaptic Exchange and Alters Intracellular Trafficking

“…Phosphorylation of gephyrin at Ser270 is mediated by CDK5 and GSK3β, while a partnering and functionally relevant Ser268 site is regulated by ERK1/2 (31). While the exact signaling mechanism responsible for gephyrin remodeling and phosphorylation in our study is unclear, we have previously shown 30 min treatment with the GABA A R agonist muscimol leads to ERK1/2/BDNF signaling, decreased gephyrin synaptic and total levels, and decreased γ2-GABA A R at synapses and potentiation by BZDs (55). Thus, changes in receptor and scaffold synaptic level and function can occur on the timescale of minutes.…”

An Analysis of Five TrkB Gene Polymorphisms in Schizophrenia and the Interaction of Its Haplotype with rs6265 BDNF Gene Polymorphism

“…The SNPs of the TrkB gene were associated with the emotional arousal or the impulsivity phenotypes in healthy people [18,23]. It was found that the BDNF-TrkB signaling affects the plasticity mechanisms at the GABAergic synapses [10]. In schizophrenia, several alterations were revealed in GABA neurotransmission.…”

“…It has been revealed that this receptor might prompt the synthesis of gamma amino butyric acid (GABA) and the expression of the glutamate receptors. Additionally, schizophrenia is connected with a dysfunction of the GABA neurotransmission [10].…”

A physiological role for GABAAreceptor desensitization – induction of long-term potentiation at inhibitory synapses

“…Some previous studies of agonist-dependent plasticity at inhibitory synapses have suggested the involvement of underlying mechanisms that require depolarising currents mediated by GABAARs to induce Ca 2+ signalling 29,45 . These studies have associated depolarising GABAcurrents with reduced synaptic efficacy.…”

“…Nevertheless, many studies have focused on changes to the receptor following sustained activation with agonists or allosteric modulators 17 . These changes include: phosphorylation of receptor subunits [18][19][20][21] , altered expression of GABAARs 18,21-28 , changes to receptor mobility and clustering 26,[29][30][31] , and alterations to receptor pharmacology 32 .…”