Abstract
Psychiatric diseases, including schizophrenia, bipolar disorder and major depression, are projected to lead global disease burden within the next decade. Pharmacotherapy, the primary – albeit often ineffective – treatment method, has remained largely unchanged over the past 50 years, highlighting the need for novel target discovery and improved mechanism-based treatments. Here, we examined in wild type mice the impact of chronic, systemic treatment with Compound 60 (Cpd-60), a slow-binding, benzamide-based inhibitor of the class I histone deacetylase (HDAC) family members, HDAC1 and HDAC2, in mood-related behavioral assays responsive to clinically effective drugs. Cpd-60 treatment for one week was associated with attenuated locomotor activity following acute amphetamine challenge. Further, treated mice demonstrated decreased immobility in the forced swim test. These changes are consistent with established effects of clinical mood stabilizers and antidepressants, respectively. Whole-genome expression profiling of specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from mice treated with Cpd-60 identified gene expression changes, including a small subset of transcripts that significantly overlapped those previously reported in lithium-treated mice. HDAC inhibition in brain was confirmed by increased histone acetylation both globally and, using chromatin immunoprecipitation, at the promoter regions of upregulated transcripts, a finding consistent with in vivo engagement of HDAC targets. In contrast, treatment with suberoylanilide hydroxamic acid (SAHA), a non-selective fast-binding, hydroxamic acid HDAC 1/2/3/6 inhibitor, was sufficient to increase histone acetylation in brain, but did not alter mood-related behaviors and had dissimilar transcriptional regulatory effects compared to Cpd-60. These results provide evidence that selective inhibition of HDAC1 and HDAC2 in brain may provide an epigenetic-based target for developing improved treatments for mood disorders and other brain disorders with altered chromatin-mediated neuroplasticity.
Highlights
Epigenetic mechanisms involving chromatin-modifying enzymes and remodeling factors are increasingly implicated in the pathophysiology of mood disorders including depression and bipolar disorder, as well as in other psychiatric diseases such as schizophrenia [1]
We assessed these parameters for suberoylanilide hydroxamic acid (SAHA) (Fig. 1a), a non-selective inhibitor of class I and class II Histone deacetylase (HDAC) subtypes that has been demonstrated in mice to enhance cognition following chronic systemic treatment [28] and improve depression-related behaviors when directly infused into brain [3]
To determine whether the binding kinetics of Compound 60 (Cpd-60) and SAHA correlated with changes in cellular HDAC activity over time, we examined the acetylation of histone H4 at lysine 12 (H4K12ac) by western blot in HEK293 cells exposed to Cpd-60 or SAHA
Summary
Epigenetic mechanisms involving chromatin-modifying enzymes and remodeling factors are increasingly implicated in the pathophysiology of mood (affective) disorders including depression and bipolar disorder, as well as in other psychiatric diseases such as schizophrenia [1]. Neuroplasticity – the capacity for changes in brain function – is relevant to understanding both disease states and effective treatment mechanisms These changes involve dynamic modulation of chromatin– DNA packaged around octameric cores of histone proteins H2A, H2B, H3 and H4 which is subject to diverse post-translational modifications. Histone deacetylase (HDAC) enzymes, including subtypes comprising class I (HDAC1, 2, 3 and 8) and class II (HDAC 4–7, 9 and 10), control the deacetylation of histone and non-histone proteins. These enzymes are important mediators in epigenetic regulation of gene expression that may contribute to mechanisms underlying psychopathology and treatment
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