Hsiao Ya-Hsin, Hung Hui-Chi, Yu Yang-Jung, Su Chun-Lin, Chen Shun-Hua, Gean Po-Wu
Department of Pharmacology, College of Medicine, National Cheng Kung University, Taiwan.
Microbiology and Immunology, College of Medicine, National Cheng Kung University, Taiwan.
Neurobiol Learn Mem. 2017 May;141:1-8. doi: 10.1016/j.nlm.2017.02.020. Epub 2017 Mar 6.
Co-housing with a company exerts profound effects on memory decline in animal model of Alzheimer's disease (AD). Recently, we found that APP/PS1 mice of 9-month-old improved their memories after co-housing with wide-type mice for 3months by increasing hippocampal brain-derived neurotrophic factor (BDNF) expression. However, the mechanism of how co-housing could induce BDNF expression remains elusive. Here we examined epigenetic changes in the mouse hippocampus that accompanied the co-housing-induced memory improvement. We found that the level of histone deacetylase 2 (HDAC2), but not that of HDAC1, was significantly lower in the memory improved mice than in the control and memory un-improved APP/PS1 mice after co-housing. Knockdown of Hdac2 resulted in a higher freezing response after co-housing. Conversely, over-expression of HDAC2 blocked co-housing-induced memory improvement. The level of Bdnf exon IV mRNA increased significantly after knockdown of Hdac2. ChIP assay revealed a decreased occupancy of HDAC2 in the promoter region of Bdnf exon IV of memory improved mice but not memory un-improved and control APP/PS1 mice. Consistently, the acetylation of histone 3 on Lys 9 (H3K9) and histone 4 on Lys12 (H4K12) increased significantly in the promoter region of Bdnf exon IV. These results suggest HDAC2 expression is reduced after co-housing resulting in a decreased occupancy of HDAC2 and increased histone H3K9 and H4K12 acetylation in the promoter region of Bdnf exon IV, leading to increased BDNF expression in the hippocampus that improves memory.
与同伴共同饲养对阿尔茨海默病（AD）动物模型的记忆衰退具有深远影响。最近，我们发现9月龄的APP/PS1小鼠在与野生型小鼠共同饲养3个月后，通过增加海马脑源性神经营养因子（BDNF）的表达改善了记忆。然而，共同饲养如何诱导BDNF表达的机制仍不清楚。在此，我们研究了与共同饲养诱导的记忆改善相关的小鼠海马体表观遗传变化。我们发现，共同饲养后，记忆改善的小鼠中组蛋白去乙酰化酶2（HDAC2）的水平显著低于对照组和记忆未改善的APP/PS1小鼠，而HDAC1的水平则无此变化。敲低Hdac2会导致共同饲养后出现更高的僵住反应。相反，HDAC2的过表达则会阻碍共同饲养诱导的记忆改善。敲低Hdac2后，Bdnf外显子IV的mRNA水平显著增加。染色质免疫沉淀分析显示，记忆改善的小鼠中，HDAC2在Bdnf外显子IV启动子区域的占有率降低，而记忆未改善的APP/PS1小鼠和对照组小鼠则无此现象。一致的是，Bdnf外显子IV启动子区域的组蛋白3赖氨酸9（H3K9）和组蛋白4赖氨酸12（H4K12）的乙酰化显著增加。这些结果表明，共同饲养后HDAC2表达降低，导致HDAC2在Bdnf外显子IV启动子区域的占有率降低，组蛋白H3K9和H4K12乙酰化增加，从而导致海马体中BDNF表达增加，改善记忆。
