title: Long-term memory deficits in Huntington's disease are associated with reduced CBP histone acetylase activity.
abstract: 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.
authors: Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
authors: A
authors: A
authors: Giralt
authors: M
authors: M
authors: Puigdellívol
authors: O
authors: O
authors: Carretón
authors: P
authors: P
authors: Paoletti
authors: J
authors: J
authors: Valero
authors: A
authors: A
authors: Parra-Damas
authors: C A
authors: CA
authors: Saura
authors: J
authors: J
authors: Alberch
authors: S
authors: S
authors: Ginés
mesh_terms: D000107:Acetylation; D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western; D050882:CREB-Binding Protein / Q000502:physiology*; D003072:Cognition Disorders / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D016762:Genes, fos; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D051548:Histone Acetyltransferases / Q000172:deficiency*; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology* / Q000473:pathology*; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008297:Male; D018782:Maze Learning; D057567:Memory, Long-Term; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger; D050882:CREB-Binding Protein; D051548:Histone Acetyltransferases