This project is part of our laboratory's long-term efforts to elucidate the molecular mechanisms responsible for resilience to depression and antidepressant (ATD) efficacy. A greater understanding of these mechanisms is critical to the discovery of novel and more effective antidepressant therapies. Histone deacetylase (HDAC) inhibitors, drugs that promote protein hyperacetylation in the brain, have demonstrated consistent behavioral activity in rodent models of stress-related disorders. Thus far, most studies have interpreted the antidepressant-like profile of HDAC inhibitors (HDACi) in the context of chromatin-remodeling mechanisms. However, it is now well established that the influence of lysine acetylation extends far beyond transcriptional regulation. In fact recent proteomic examinations indicate that histones represent only a fraction of the the acetylome. To determine which mechanisms constitute bona fide mediators of the antidepressant activity of HDACi, it is now crucial to examine the participation of non- histone substrates of HDACs in murine models of depression and stress resiliency. HDAC6 is an HDAC family member which, in neurons, localizes exclusively to the cytoplasm. This feature makes it a first line candidate to mediate effects of HDACi on non-histone proteins. Studies conducted by other groups in non-neuronal systems have shown that HDAC6 is an important modulator of the glucocorticoid receptor (GR) chaperone complex required for proper corticosteroid signaling. Our laboratory has found that HDAC6 is particularly enriched in serotonergic neurons, and we have reported that mice lacking HDAC6 in these cells show increased behavioral resilience. Here we propose to test the hypothesis that HDAC6 regulation of GR signaling mediates the effect of the HDAC6 KO on resilience. We will do this by examining the effects of loss of HDAC6 on GR-mediated gene transcription using laser capture microdissection and microarray technology. We will also examine differences in corticosterone-induced behavioral changes in mice lacking HDAC6 specifically in serotonin neurons. These results could provide an important new target for the treatment of depression and other stress-related disorders, which currently present a significant economic and societal burden. PUBLIC HEALTH RELEVANCE: This proposal seeks to examine the value of HDAC6 as a novel target for antidepressant and pro-resilience interventions. For a subset of patients suffering from depression and posttraumatic stress disorder, there are currently no effective treatments. If our hypothesis that loss of HDAC6 enhances resilience to stress via inhibition of glucocorticoid signaling proves correct, it could open a promising new avenue of therapeutic interventions for these disorders.