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

Hum Mol Genet. 2012 Mar 15;21(6):1203-16. doi: 10.1093/hmg/ddr552. Epub 2011 Nov 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Behavior, Animal
  • Blotting, Western
  • CREB-Binding Protein / physiology*
  • Cognition Disorders / etiology
  • Cognition Disorders / pathology
  • Disease Models, Animal*
  • Female
  • Genes, fos
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Histone Acetyltransferases / deficiency*
  • Humans
  • Huntington Disease / enzymology*
  • Huntington Disease / pathology*
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Male
  • Maze Learning
  • Memory, Long-Term*
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction


  • RNA, Messenger
  • CREB-Binding Protein
  • Histone Acetyltransferases