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

A Giralt1, M Puigdellívol, O Carretón

  • 1Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.

Human Molecular Genetics
|November 26, 2011
PubMed

Insights

Huntington's disease (HD) causes early memory deficits in mice due to reduced CREB-binding protein (CBP). Histone deacetylase inhibitors restored memory function, suggesting a new therapeutic approach for HD cognitive impairment.

Area of Science:

  • Neurodegenerative Diseases
  • Genetics
  • Epigenetics
  • Cognitive Neuroscience

Background:

  • Huntington's disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion in the huntingtin gene.
  • While known for motor symptoms, early cognitive deficits precede motor disturbances in HD patients.

Purpose of the Study:

  • To investigate early cognitive impairments in a mouse model of Huntington's disease.
  • To explore the molecular mechanisms underlying cognitive deficits in HD, focusing on CREB-binding protein (CBP) and histone acetylation.
  • To evaluate the therapeutic potential of histone deacetylase inhibitors for HD-related memory dysfunction.

Main Methods:

  • Utilized heterozygous HD knock-in mutant mice (Hdh(Q7/Q111)) as an accurate model for HD.
  • Assessed long-term spatial and recognition memory in Hdh(Q7/Q111) mice.
  • Measured hippocampal expression of CBP, histone H3 acetylation, and CREB/CBP target genes (e.g., c-fos, Arc, Nr4a2).
  • Administered the histone deacetylase inhibitor trichostatin A to Hdh(Q7/Q111) mice and evaluated its effect on memory and gene transcription.

Main Results:

  • Hdh(Q7/Q111) mice exhibited impaired long-term spatial and recognition memory.
  • Cognitive deficits correlated with reduced hippocampal CBP expression and histone H3 acetylation.
  • Expression of key CREB/CBP target genes involved in memory was significantly decreased in Hdh(Q7/Q111) mice.
  • Treatment with trichostatin A rescued recognition memory deficits and normalized transcription of selective CREB/CBP target genes.

Conclusions:

  • CREB-binding protein (CBP) plays a critical role in the cognitive dysfunction observed in Huntington's disease.
  • Reduced CBP levels and histone acetylation contribute to memory deficits in HD.
  • Histone deacetylase inhibitors represent a promising therapeutic strategy for treating memory impairments in Huntington's disease.

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