title: A selective HDAC 1/2 inhibitor modulates chromatin and gene expression in brain and alters mouse behavior in two mood-related tests.
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.
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Frederick A
authors: FA
authors: Schroeder
authors: Michael C
authors: MC
authors: Lewis
authors: Daniel M
authors: DM
authors: Fass
authors: Florence F
authors: FF
authors: Wagner
authors: Yan-Ling
authors: YL
authors: Zhang
authors: Krista M
authors: KM
authors: Hennig
authors: Jennifer
authors: J
authors: Gale
authors: Wen-Ning
authors: WN
authors: Zhao
authors: Surya
authors: S
authors: Reis
authors: Douglas D
authors: DD
authors: Barker
authors: Erin
authors: E
authors: Berry-Scott
authors: Sung Won
authors: SW
authors: Kim
authors: Elizabeth L
authors: EL
authors: Clore
authors: Jacob M
authors: JM
authors: Hooker
authors: Edward B
authors: EB
authors: Holson
authors: Stephen J
authors: SJ
authors: Haggarty
authors: Tracey L
authors: TL
authors: Petryshen
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000339:Affect / Q000187:drug effects*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002843:Chromatin / Q000187:drug effects* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology; D008297:Male; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D015203:Reproducibility of Results; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D001549:Benzamides; D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D008094:Lithium; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex
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