Journal
HUMAN MOLECULAR GENETICS
Volume 21, Issue 6, Pages 1203-1216Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddr552
Keywords
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Funding
- Ministerio de Ciencia e Innovacion [SAF2009-07077, SAF2011-29507, SAF2010-20925]
- Centro de Investigaciones Biomedicas en Red sobre Enfermedades Neurodegenerativas (CIBERNED) [CB06/05/0054, CB06/05/0042]
- Fondo de Investigaciones Sanitarias Instituto de Salud Carlos III [RETICS: RD06/0010/0006]
- Fundacio La Marato de TV3
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Huntingtons disease (HD) is an autosomal dominant progressive neurodegenerative disorder caused by an expanded CAG/polyglutamine repeat in the coding region of the huntingtin (htt) gene. Although HD is classically considered a motor disorder, there is now considerable evidence that early cognitive deficits appear in patients before the onset of motor disturbances. Here we demonstrate early impairment of long-term spatial and recognition memory in heterozygous HD knock-in mutant mice (Hdh(Q7/Q111)), a genetically accurate HD mouse model. Cognitive deficits are associated with reduced hippocampal expression of CREB-binding protein (CBP) and diminished levels of histone H3 acetylation. In agreement with reduced CBP, the expression of CREB/CBP target genes related to memory, such c-fos, Arc and Nr4a2, was significantly reduced in the hippocampus of Hdh(Q7/Q111) mice compared with wild-type mice. Finally, and consistent with a role of CBP in cognitive impairment in Hdh(Q7/Q111) mice, administration of the histone deacetylase inhibitor trichostatin A rescues recognition memory deficits and transcription of selective CREB/CBP target genes in Hdh(Q7/Q111) mice. These findings demonstrate an important role for CBP in cognitive dysfunction in HD and suggest the use of histone deacetylase inhibitors as a novel therapeutic strategy for the treatment of memory deficits in this disease.
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