An Essential Role for Histone Deacetylase 4 in Synaptic Plasticity and Memory Formation

Abstract

Histone deacetylases (HDACs), a family of enzymes involved in epigenetic regulation, have been implicated in the control of synaptic plasticity, as well as learning and memory. Previous work has demonstrated administration of pharmacological histone deacetylase (HDAC) inhibitors, primarily those targeted to Class I HDACs, enhance learning and memory as well as long-term potentiation. However, a detailed understanding of the role of Class II HDACs in these processes remains elusive. Here, we show that selective loss of Hdac4 in brain results in impairments in hippocampal-dependent learning and memory and long-term synaptic plasticity. In contrast, loss of Hdac5 does not impact learning and memory demonstrating unique roles in brain for individual Class II HDACs. These findings suggest that HDAC4 is a crucial positive regulator of learning and memory, both behaviorally and at the cellular level, and that inhibition of Hdac4 activity may have unexpected detrimental effects to these processes.

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…The overexpression of HDAC1 in the adult mouse hippocampus increased this specific form of learning [185]. Furthermore, the loss of HDAC4 (in 2-month-old mice) and HDAC5 (in 10-but not 2-month-old mice) impaired memory functions, with an alteration in the CxFC and the MWM tasks in both cases [186,187].…”

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

“…However, the recent evidence has indicated that HDAC4-null mice display premature ossification of developing bones due to ectopic and early onset chondrocyte hypertrophy, but overexpression of HDAC4 in proliferating chondrocytes in vivo inhibits chondrocyte hypertrophy and differentiation (40). In addition, selective loss of HDAC4 in the brain results in impairments in hippocampaldependent learning and memory and long-term synaptic plasticity (18). These observations may suggest that HDAC4 plays a different function in different disease models.…”

Epigenetics of Brain Disorders: The Paradigm of Alzheimer ’s Disease

“…Histone modifications are present in AD [9,15,16,63,73] ; (ix) nuclear translocation of EP300 interacting inhibitor of differentiation 1 (EID1), a CBP/p300 inhibitory protein, is increased in the cortical neurons of AD patients, and overexpression of EID1 is reported to reduce hippocampal LTP and to impair cognitive function via inhibiting CBP/p300 acetyl trasferase activity and disrupting neuronal structure [83]; (x) memory formation leads to a transient increase in acetylation on lysine residues within H2B, H3, H4 [84,85]; (xi) inhibition of HDAC induces dendritic sprouting, increases synaptic number, and improves long-term memory [86]; (xii) overexpression of neuronal HDAC2 decreases dendritic spine density, synapse number, synaptic plasticity and memory formation, and HDAC2 deficiency increases synapse number and memory facilitation [87,88]; (xiii) HDAC4 is involved in learning and synaptic plasticity, and selective inhibition of HDAC4 activity may deteriorate learning and memory [89]; (xiv) treatment of hippocampal neurons with HDAC inhibitors facilitates Bdnf expression via hyper acetylation of histones at the Bdnf promoters [90,91]; (xv) histone(H3K4) methylation participates in the regulation of Bdnf expression and memory formation [92]; (xvi) histone methylation also facilitates memory consolidation coupled with histone acetylation; inhibition of HDACs with sodium butyrate (NaB) causes an increase in H3K4 trimethylation and a decrease in H3K9 dimethylation in the hippocampus after fear conditioning [92]; (xvii) histone H3 acetylation, methylation and phosphorylation is increased in the prefrontal cortex of Tg2576 mice, and histone H4 acetylation is increased in the hippocampal CA1 neurons of these transgenic mice [15,16,93].…”

“…Histone modifications are present in AD [9,15,16,63,73]: (i) histone acetylation is reduced in AD brain tissues [74] and in AD transgenic models [63]; (ii) levels of HDAC6, a tau-interacting protein and a potential modulator of tau phosphorylation and accumulation, are increased in cortical and hippocampal regions in AD [75]; (iii) SIRT1 is decreased in the parietal cortex of AD patients, and the accumulation of Aβ and tau in AD brains might be related to the loss of SIRT1 [76], since SIRT1 may reduce Aβ production, activating the transcription of ADAM10 [77]; (iv) in the brains of twins discordant for AD, tri methylation of H3K9, a marker of gene silencing, and condensation of heterochromatin structure, are increased in the temporal cortex and hippocampus of the AD twin as compared to the twin devoid of AD neuropathology [78]; (v) phosphorylation of H3S10, a key regulator in chromatin compaction during cell division, is increased in the cytoplasm of hippocampal neurons in AD cases [79]; (vi) evidence of DNA damage, as reflected by phosphorylated H2AX at Ser139, is present in hippocampal astrocytes of AD patients [80]; (vii) long-term potentiation (LTP) and memory deficits in APP/PS1 transgenic mice might be mediated in part by decreased H4 acetylation; improving histone acetylation level restores learning after synaptic dysfunction [81]; (viii) acetylation of H3 and H4 is increased in 3xTg-AD neurons relative to non-transgenic neurons [82]; (ix) nuclear translocation of EP300 interacting inhibitor of differentiation 1 (EID1), a CBP/p300 inhibitory protein, is increased in the cortical neurons of AD patients, and overexpression of EID1 is reported to reduce hippocampal LTP and to impair cognitive function via inhibiting CBP/p300 acetyl trasferase activity and disrupting neuronal structure [83]; (x) memory formation leads to a transient increase in acetylation on lysine residues within H2B, H3, H4 [84,85]; (xi) inhibition of HDAC induces dendritic sprouting, increases synaptic number, and improves long-term memory [86]; (xii) overexpression of neuronal HDAC2 decreases dendritic spine density, synapse number, synaptic plasticity and memory formation, and HDAC2 deficiency increases synapse number and memory facilitation [87,88]; (xiii) HDAC4 is involved in learning and synaptic plasticity, and selective inhibition of HDAC4 activity may deteriorate learning and memory [89]; (xiv) treatment of hippocampal neurons with HDAC inhibitors facilitates Bdnf exp...…”