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2012-03-15

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Long-term memory deficits in Huntington's disease are associated with reduced CBP histone acetylase activity

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https://doi.org/10.1093/hmg/ddr552

Resum

Huntington's 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.

Matèries

Corea de Huntington, Models animals en la investigació

Matèries (anglès)

Huntington's chorea, Animal models in research

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Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

Citació

GIRALT TORROELLA, Albert, et al. Long-term memory deficits in Huntington's disease are associated with reduced CBP histone acetylase activity. Human Molecular Genetics. 2012. Vol. 21, num. 6, pags. 1203-1216. ISSN 0964-6906. [consulted: 22 of June of 2026]. Available at: https://hdl.handle.net/2445/183388

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