Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
J Neurosci. 2012 Mar 28;32(13):4651-9. doi: 10.1523/JNEUROSCI.3308-11.2012.
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 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) Homer1a 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 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 histone deacetylation 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.
条件性恐惧的巩固涉及到长时程记忆形成所需基因的上调。一个重要的问题仍然是，这是否部分归因于表观遗传调控和染色质调节。我们检查了 Homer1a 是否是记忆形成所必需的，它是否是 BDNF-TrkB 激活的下游，以及这条途径是否利用组蛋白修饰进行活性依赖的转录调节。我们最初发现，Homer1a 敲除小鼠在条件性恐惧（5 次音调-休克呈现，70 dB，6 kHz 音调，0.5 s，0.6 mA 足底电击）中表现出缺陷。然后，我们证明：（1）在体内恐惧条件后，野生型小鼠的杏仁核和海马体中的 Homer1a mRNA 增加；（2）BDNF 应用于体外原代海马和杏仁核培养物后，其增加；（3）这些增加依赖于转录和 MAPK 信号。此外，使用染色质免疫沉淀，我们发现，体外和体内操作都导致杏仁核细胞中 Homer1 启动子 H3K9 甲基化减少，但海马细胞中 Homer1 启动子 H3 乙酰化增加。然而，在 H4 乙酰化或 H3K27 二甲基化方面没有观察到变化。组蛋白去乙酰化酶抑制剂丁酸钠增强了情境而非条件性恐惧条件，并且增强了海马中的 Homer1 H3 乙酰化。这些数据为 BDNF 诱导的可塑性和 BDNF 依赖的学习过程中 Homer1a 的动态表观遗传调节提供了证据。此外，该基因的上调可能通过海马和杏仁核中的不同表观遗传修饰来调节。
