Histone deacetylases in memory and cognition

Abstract

Over the past 30 years, lysine acetylation of histone and nonhistone proteins has become established as a key modulator of gene expression regulating numerous aspects of cell biology. Neuronal growth and plasticity are no exception; roles for lysine acetylation and deacetylation in brain function and dysfunction continue to be uncovered. Transcriptional programs coupling synaptic activity to changes in gene expression are critical to the plasticity mechanisms underlying higher brain functions. These transcriptional programs can be modulated by changes in histone acetylation, and in many cases, transcription factors and histone-modifying enzymes are recruited together to plasticity-associated genes. Lysine acetylation, catalyzed by lysine acetyltransferases (KATs), generally promotes cognitive performance, whereas the opposing process, catalyzed by histone lysine deacetylases (HDACs), appears to negatively regulate cognition in multiple brain regions. Consistently, mutation or deregulation of different KATs or HDACs contributes to neurological dysfunction and neurodegeneration. HDAC inhibitors have shown promise as a treatment to combat the cognitive decline associated with aging and neurodegenerative disease, as well as to ameliorate the symptoms of depression and posttraumatic stress disorder, among others. In this review, we discuss the evidence for the roles of HDACs in cognitive function as well as in neurological disorders and disease. In particular, we focus on HDAC2, which plays a central role in coupling lysine acetylation to synaptic plasticity and mediates many of the effects of HDAC inhibition in cognition and disease.

Metabolic Stress Induces Cognitive Disturbances and Inflammation in Aged Mice: Protective Role of Resveratrol

“…Histone deacetylases have been implicated in memory and cognition, and concretely, HDAC2 plays a central role in coupling lysine acetylation with synaptic plasticity. 46 Results demonstrated an increase in Hdac2 gene expression in old animals compared with younger ones, and notably, RV was able to reduce this deacetylase expression in both groups of old mice. In addition to cytosolic deacetylase activity, as we previously pointed out, SIRT1 is also an enzyme participating in histone deacetylation and then in the epigenetic control of gene expression, 47 and RV was able to increase Sirt1 expression in RV-fed old mice.…”

Propofol exposure during early gestation impairs learning and memory in rat offspring by inhibiting the acetylation of histone

“…The consolidation and maintenance of memory require specific genes expression, and histone acetylation promotes the expression of these genes, while histone deacetylation represses their expression 21, 43. Histone deacetylases (HDACs) inhibit the expression of these genes, while histone acetyltransferases (HATs) promote their expression 44.…”

Histone acetylation in neuronal (dys)function

“…Four principal families of HDACis exist: short chain fatty acids (sodium butyrate, phenylbutyrate, valproic acid), hydroxamic acids [trichostatin A, suberoylanilide hydroxamic acid (SAHA)], epoxyketones (trapoxin), and benzamides. Their use favors histone acetylation and they constitute promising molecules for the treatment of some pathologies where acetylation is deficient (7,34,35).…”

“…It is well established that LTP is functionally correlated to histone acetylation. LTP causes an increase of H3 and H4 acetylation (41,42) and can be potentiated by the use of HDACis (34,35,42,43). Moreover, impairment of the HAT CBP in mice decreases the overall acetylation of H2B and disrupts LTP in hippocampal slices (44)(45)(46).…”