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.

Inositol polyphosphate multikinase is a transcriptional coactivator required for immediate early gene induction

“…IPMK regulates IEGs by binding to CBP to augment its recruitment to promoters of the IEGs. Because of the importance of CBP function and IEGs for plasticity of neuronal function (22,(26)(27)(28)(29)(30)(31)(32), we suggest that IPMK is a novel determinant of mechanisms underlying learning and memory. Such a possibility is supported by the impaired performance of nestin-Cre +/− IPMK fl/fl mice in contextual habituation and the Barnes maze test.…”

Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

“…Similar results were obtained at 8 months of age in the T-SAT test, suggesting that reduced p75 NTR expression in HD mice prevented, rather than merely delayed, spatial memory deficits (Supplemental Figure 2A). We next evaluated recognition memory by using the novel object recognition test (NORT), based on the natural tendency of mice to spend more time exploring a novel object than a familiar one and known to be dependent on hippocampal and cortical circuits (45)(46)(47) (15). First, animals were tested in the elevated plus maze and the light-dark exploration paradigms to assess anxiety-related behaviors.…”

“…Actually, cytoplasmic and nuclear huntingtin aggregates within the hippocampus have been described in HD individuals (12). Importantly, such behavioral deficits, together with hippocampal long-term potentiation (LTP) disturbances, have been replicated in different HD mouse models (2,(13)(14)(15). Although altered synaptic plasticity and aberrant dendritic spine density and morphology have been proposed as underlying mechanisms (14,16,17), little is known about the precise molecular pathways involved in HD synaptic and memory disturbances.…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…For instance, CBP alterations could directly affect striatal regulations, and thereby motor impairment, influencing the transcription dependent of its binding partner CREB, a key regulator of striatal vulnerability [87]. A decrease of histone H3ac, associated with decreased CBP/CREBdependent gene expression, was observed in the hippocampus of the HdhQ7/Q111 transgenic mouse model, an event that might explain some cognitive deficits associated with HD [88]. A 30 % increase in Hdac1 expression was also observed in the cortices and striata of HD R6/2 mice, but is unlikely to be a cause of a detectable decrease in global histone acetylation [89].…”

“…However, the overexpression of PCAF was not sufficient to ameliorate the HD phenotype in transgenic flies, suggesting that therapeutic strategies aimed at increasing PCAF protein levels are likely ineffective in ameliorating HD pathology; notably, increasing the HAT activity of PCAF has not been tested, and other trials targeting PCAF activity are needed [86]. Increasing the acetylation of histones and non-histone proteins via the use of HDAC inhibitors also counteracts neurodegeneration [8,88,[99][100][101]. Intriguingly, McFarlan et al [96] also demonstrated that HDAC inhibition reestablished altered transcriptional levels in the striatum of the R6/2 mouse model, but only slightly improved H3ac binding to specific promoter, emphasizing the idea that the overall chromatin environment surrounding a gene would be more adapted to therapeutic targeting than simply increasing the acetylation of the histones.…”