Gephyrin plays a key role in BDNF-dependent regulation of amygdala surface GABAARs

• Type of Material: Article
• Authors: Liping Mou, Emory University; Brian George Dias, Emory University; Heather Gosnell, Emory University; Kerry Ressler, Emory University
• Language: English
• Date: 2013-12-26
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://www.sciencedirect.com/science/article/pii/S0306452213008300
• Title of Journal or Parent Work: Neuroscience
• ISSN: 0306-4522
• Volume: 255
• Start Page: 33
• End Page: 44
• Grant/Funding Information: Support was received from the NIH/National Center for Research Resources base grant P51RR000165 to Yerkes National Primate Research Center.; This work was supported through NIH (DA019624, MH096764(KJR)) as well as the Burroughs Wellcome Fund.
• Keywords: Consolidation; GABA; Memory; Fear; Amygdala; Gephyrin
• Research Categories: Biology, Neuroscience; Psychology, Behavioral

Abstract

Brain–derived neurotrophic factor (BDNF) is critically involved in synaptic plasticity and neurotransmission. Our lab has previously found that BDNF activation of TrkB is required for fear memory formation and that GABAA receptor subunits and the GABAA clustering protein gephyrin are dynamically regulated during fear memory consolidation. We hypothesize that TrkB-dependent internalization of GABAA receptors may partially underlie a transient period of amygdala hyperactivation during fear memory consolidation. We have previously reported that BDNF modulates GABAA receptor α1 subunit sequestration in cultured hippocampal and amygdala neurons by differential phosphorylation pathways. At present, no studies have investigated the regulation of gephyrin and GABAA receptor α1 subunits following BDNF activation in amygdala. In this study, we confirm the association of GABAA receptor α1 and γ2 subunits with gephyrin on mouse amygdala neurons by coimmunoprecipitation and immunocytochemistry. We then demonstrate that rapid BDNF treatment, as well as suppression of gephyrin protein levels on amygdala neurons, induced sequestration of surface α1 subunits. Further, we find that rapid exposure of BDNF to primary amygdala cultures produced decreases in gephyrin levels, whereas longer exposure resulted in an eventual increase. While total α1 subunit levels remained unchanged, gephyrin was downregulated in whole cell homogenates, but enhanced in complexes with GABAA receptors. Our data with anisomycin suggest that BDNF may rapidly induce gephyrin protein degradation, with subsequent gephyrin synthesis occurring. Together, these findings suggest that gephyrin may be a key factor in BDNF-dependent GABAA receptor regulation in amygdala. This work may inform future studies aimed at elucidating the pathways connecting BDNF, GABAA systems, gephyrin, and their role in underlying amygdala-dependent learning.