The Role of Chromatin Remodeling in Hippocampus in Depression and Antidepressant Action
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This thesis presents a novel level by which neuroplastic changes in the brain may be disrupted with depression and reversed by treatment with antidepressants: regulation at the level of chromatin remodeling. The technique of brain chromatin immunoprecipitation was pioneered to directly measure the in vivo modifications of histones, a form of chromatin remodeling, at gene promoter regions in the hippocampus after chronic defeat stress, a model of depression, and chronic treatment with the antidepressants imipramine and electroconvulsive seizure (ECS). Chromatin modifications and transcriptional changes were assayed in one gene in particular, the brain-derived neurotrophic factor (BDNF). BDNF is alternatively spliced to generate several mRNA transcripts, driven by unique promoters. I measured the expression levels of each BDNF transcript (I-IV) in rat after ECS, as well as each BDNF transcript (I-V) in mice after chronic stress and imipramine treatments, and found that these chronic treatments induce lasting changes in the expression of specific BDNF splice variants. These changes correlated with sustained modifications in histones at the exact promoter regions, driving the differential changes in BDNF expression. Chronic defeat stress induced robust enrichment of H3-K27 methylation at BDNF P3 and P4 promoters (modifications expected to repress promoter activity), while chronic imipramine in defeated animals lead to lasting upregulation in the levels of H3 acetylation and H3-K4 methylation at P3 and P4 (modifications expected to stimulate promoter activity). Finally, I discovered a novel role for the histone deacetylase HDAC5 in the therapeutic efficacy of chronic imipramine after defeat stress. I found that chronic imipramine downregulates HDAC5 after stress, that HDAC5 overexpression in the hippocampus blocks the behavioral effects of imipramine in defeated mice, that HDAC5 inhibition exerts a subtle antidepressant-like effect, and that HDAC5 deficiency reduces the pathological response to stress. This unexpected role for HDAC5 provides an important mechanistic link between the adaptive chromatin remodeling changes at genes and the ability of chronic antidepressants to exert therapeutic efficacy after chronic stress. These experiments provide one of the first endeavors to understand the role of chromatin remodeling in modulating long-term adaptive changes in brain associated with complex psychiatric conditions, such as depression.