Epigenetic modulation of homer1a transcription regulation in amygdala and hippocampus with Pavlovian fear conditioning

• Type of Material: Article
• Authors: Amy L. Mahan, Emory University; Liping Mou, Emory University; Nirali Shah, Emory University; Jia Hua Hu, Johns Hopkins School of Medicine; Paul Worley, Johns Hopkins School of Medicine; Kerry Ressler, Emory University
• Language: English
• Date: 2012-03-28
• Publisher: Society for Neuroscience
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 the authors
• Final Published Version (URL): http://dx.doi.org/10.1523%2FJNEUROSCI.3308-11.2012
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0270-6474
• Volume: 32
• Issue: 13
• Start Page: 4651
• End Page: 4659
• Grant/Funding Information: Support was provided by NIH Grants DA019624 and P30 NS055077, the Burroughs Wellcome Fund, the Center for Behavioral Neuroscience, a Science and Technology Center program of the National Science Foundation under Agreement No. IBN-9876754, National Primate Research Center Base Grant No. RR-00165, and the Animal Resource Program at NIH.
• Research Categories: Psychology, Behavioral

Abstract

The consolidation of conditioned fear involves upregulation of genes necessary for long-term memory formation. An important question remains as to whether this results in part from epigenetic regulation and chromatin modulation. We examined whether homer1a, which is required for memory formation, is necessary for Pavlovian cued fear conditioning, whether it is downstream of BDNF - TrkB activation, and whether this pathway utilizes histone modifications for activity-dependent transcriptional regulation. We initially found that Homer1a ko mice exhibited deficits in cued fear conditioning (5 tone-shock presentations with 70 dB, 6kHz tones and 0.5s, 0.6mA footshocks). We then demonstrate that homer1a mRNA 1) increases after fear conditioning in vivo within both amygdala and hippocampus of wild type mice, 2) increases after BDNF application to primary hippocampal and amygdala cultures in vitro, and 3) these increases are dependent on transcription and MAPK signaling. Furthermore, using chromatin immunoprecipitation we found that both in vitro and in vivo manipulations result in decreases in homer1 promoter H3K9 methylation in amygdala cells but increases in homer1 promoter H3 acetylation in hippocampal cells. However no changes were observed in H4 acetylation or H3K27 dimethylation. Inhibition of H3 acetylation by sodium butyrate enhanced contextual but not cued fear conditioning and enhanced homer1 H3 acetylation in the hippocampus. These data provide evidence for dynamic epigenetic regulation of homer1a following BDNF-induced plasticity and during a BDNF-dependent learning process. Furthermore, upregulation of this gene may be regulated through distinct epigenetic modifications in the hippocampus and amygdala.