Epigenetic Modulation of Homerla Transcription Regulation in Amygdala and Hippocampus with Pavlovian Fear Conditioning

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 Homerla, 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 Homerla knock-out mice exhibited deficits in cued fear conditioning (5 tone-shock presentations with 70 dB, 6 kHz tones and 0.5 s, 0.6 mA footshocks). We then demonstrated that: (1) Homerla mRNA increases after fear conditioning in vivo within both amygdala and hippocampus of wild-type mice; (2) it 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 Homerl promoter H3K9 methylation in amygdala cells but increases in Homerl promoter H3 acetylation in hippocampal cells. However, no changes were observed in H4 acetylation or H3K27 dimethylation. Inhibition of histone deacetylation by sodium butyrate enhanced contextual but not cued fear conditioning and enhanced Homerl H3 acetylation in the hippocampus. These data provide evidence for dynamic epigenetic regulation of Homerla 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.