DOI: 10.1101/514133Jan 8, 2019Paper

Diazepam Accelerates GABAAR Synaptic Exchange and Alters Intracellular Trafficking

BioRxiv : the Preprint Server for Biology
Joshua M. Lorenz-GuertinTija C. Jacob

Abstract

Despite 50+ years of clinical use as anxiolytics, anti-convulsants, and sedative/hypnotic agents, the mechanisms underlying benzodiazepine (BZD) tolerance are poorly understood. BZDs potentiate the actions of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, through positive allosteric modulation of γ2 subunit containing GABA type A receptors (GABAARs). Here we define key molecular events impacting γ2 GABAAR and the inhibitory synapse gephyrin scaffold following initial sustained BZD exposure in vitro and in vivo. Using immunofluorescence and biochemical experiments, we found that cultured cortical neurons treated with the classical BZD, diazepam (DZP), presented no substantial change in surface or synaptic levels of γ2-GABAARs. In contrast, both γ2 and the postsynaptic scaffolding protein gephyrin showed diminished total protein levels following a single DZP treatment in vitro and in mouse cortical tissue. We further identified DZP treatment enhanced phosphorylation of gephyrin Ser270 and increased generation of gephyrin cleavage products. Selective immunoprecipitation of γ2 from cultured neurons revealed enhanced ubiquitination of this subunit following DZP exposure. To assess novel t...Continue Reading

Related Concepts

Brain
Cerebral Cortex
Diagnostic Imaging
Diazepam
Down-Regulation
Gamma-Aminobutyric Acid
Gene Clusters
Immunoprecipitation
Lysosomes
Laboratory mice

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