Cognitive Function in Health and Disease: The Role of Epigenetic Mechanisms

Abstract

Epigenetic mechanisms regulate the interaction between the genome and the environment and have been implicated in the etiology of various brain diseases. One type of epigenetic modification, histone acetylation, is dynamically altered during memory formation. Histone acetylation is regulated by the activities of histone deacetylase (HDAC) and histone acetyltransferase enzymes. The use of HDAC inhibitors has emerged as a promising new strategy for the therapeutic intervention of neurodegenerative disease. We used a combination of pharmacological and mouse genetic approaches that allowed us to identify HDAC2 as a specific negative regulator of synaptic plasticity and memory formation. Our results suggest that HDAC inhibitors enhance cognitive function by inhibiting HDAC2, which renders HDAC2 target genes more accessible to transcriptional activators and coactivators recruited by neuronal activity stimulation. The data presented at the 2011 Barcelona ADPD Conference delineate a novel and important role for HDAC2 activity in the cognitive impairments associated with neurodegenerative disease.

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Neurodegenerative Dis
DOI: 10.1159/000334602
Cognitive Function in Health and Disease:
The Role of Epigenetic Mechanisms
Alison E. Mungenast a Li-Huei Tsai a–c
a Picower Institute for Learning and Memory,
b Department of Brain and Cognitive Sciences, Massachusetts Institute
of Technology, and
c Howard Hughes Medical Institute, Cambridge, Mass. , USA
The Epigenetic Regulation of Gene Transcription
Epigenetic mechanisms, such as histone modification
and DNA methylation, are key regulators of gene-envi-
ronment interactions and have been implicated in the eti-
ology of various brain diseases [for a review, see ref.
1 ].
One common form of epigenetic modification is histone
acetylation, which is dynamically altered during memory
formation
[2] . Long-lasting forms of synaptic plasticity
involve changes in the expression of genes involved in
synaptic functioning [for a review, see ref.
3 ] and, in re-
cent years, accumulating evidence indicates that epige-
netic mechanisms play crucial roles in promoting these
long-lasting changes
[4] .
Histone proteins may become acetylated on lysine res-
idues. The addition of an acetyl group leads to a relax-
ation of the chromatin that has been associated with tran-
scriptional activation
[5] . Histone acetylation is regulated
by the opposing activities of histone deacetylase (HDAC)
and histone acetyltransferase enzymes
[6, 7] . Class I
HDACs are primarily found within the nucleus, where
they regulate histone acetylation and suppress gene ex-
pression
[8] . Alterations in histone acetylation have re-
cently been shown to have an important role during
learning and memory processes. Numerous laboratories
have shown that pharmacological HDAC inhibitors
Key Words
Alzheimer’s disease ⴢ Synaptic plasticity ⴢ Learning and
memory ⴢ Epigenetics ⴢ Chromatin ⴢ Histone deacetylase
Abstract
Epigenetic mechanisms regulate the interaction between
the genome and the environment and have been implicated
in the etiology of various brain diseases. One type of epige-
netic modification, histone acetylation, is dynamically al-
tered during memory formation. Histone acetylation is regu-
lated by the activities of histone deacetylase (HDAC) and his-
tone acetyltransferase enzymes. The use of HDAC inhibitors
has emerged as a promising new strategy for the therapeutic
intervention of neurodegenerative disease. We used a com-
bination of pharmacological and mouse genetic approaches
that allowed us to identify HDAC2 as a specific negative reg-
ulator of synaptic plasticity and memory formation. Our re-
sults suggest that HDAC inhibitors enhance cognitive func-
t io n b y in hi b it i ng HD AC 2 , w hi c h r e nd er s HD AC 2 ta rg e t g e ne s
more accessible to transcriptional activators and coactiva-
tors recruited by neuronal act ivit y stimu lation . The data pre-
sented at the 2011 Barcelona ADPD Conference delineate a
novel and important role for HDAC2 activity in the cognitive
impairments associated with neurodegenerative disease.
Copyr ight © 2012 S. Karger AG, Ba sel
Recei ved: July 1, 2011
Accepted a fter revision: November 25, 2011
Publish ed online: February 1, 2012
Diseases
Li-Huei Tsai
Howard Hughes Medical Ins titute
77 Massachusetts Avenue
Cambridge, M A 02139 (USA)
E-Mail lhtsai  @  mit.edu
© 2012 S. Ka rger AG, Basel
1660–2854/12/0000–0000$38.00/0
Accessible online at:
www.karger.com/ndd
© Free Author
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sonal use only
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ARTICLE WITHOUT WRITTEN
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Mungenast  /Tsai 
Neurodegenerative Dis
2
(HDACis) improve cognition in both wild-type animals
and in animal models of neurological disease, and that
HDACis targeting class I HDACs (HDACs 1, 2, 3 and 8),
such as suberoylanilide hydroxamic acid (SAHA), are the
most effective in enhancing cognitive function [for a re-
view, see ref.
9 ]. Guan et al. [4] used SAHA-based affinity
probes
[10] to identify the closely related HDAC1 and
HDAC2 as the main cellular targets of SAHA, followed
by a genetic approach to dissect out the contribution
of HDAC2 versus HDAC1 to cognitive function. These
studies show that transgenic mice that have a neuron-
specific overexpression of HDAC2 exhibit striking im-
pairments in memory formation and synaptic plasticity
that ar e not obser ved i n HDAC1-overex press ing mic e
[4] .
HDAC2 knockout (KO) mice, but not HDAC1 KO mice,
exhibit enhanced synaptic plasticity and facilitated learn-
ing and memory, and serve as a rare genetic model of
cognitive enhancement. These findings indicate that
HDAC2 plays a major role in learning and memory and
synaptic plasticity, as well as in the acetylation of the age-
associated H4K12 residue.
p25/Cdk5 and Neurodegeneration
The proline-directed serine/threonine kinase, Cdk5,
has been well characterized as a tau kinase
[11, 12] that
associates with neurofibrillary tangles in the brain of
Alzheimer’s disease (AD) patients
[13 , 14] . The activation
of Cdk5 results from its association with one of two acti-
vators, p35 or p39
[15 , 16] . The truncated form of p35, p25,
was shown to be increased in the brains of AD patients
[17,
18] , and the increased generation of p25 was subsequently
found in mouse models of AD [for a review, see ref.
19 ],
ischemia
[20] , amyotrophic lateral sclerosis [21] , Parkin-
son’s disease [22] , Huntington’s disease [23] , and hippo-
campal sclerosis
[24] . The cleavage of p35 to p25 is induced
in primary neurons upon exposure to a number of neuro-
toxic insults, which include oxidative stress (H
2 O 2 ), exci-
totoxicity ( glutamate), high interna l calcium (ionophores),
and ␤ -amyloid protein
[20] . Therefore, p25 generation is
associated with neurotoxicity both in vitro and in vivo.
The bi-transgenic CK-p25 mouse model of neurode-
generation expresses a p25- green fluorescent protein fu-
sion protein in an inducible, postnatal and forebrain-spe-
cific manner
[25] . Upon the induction of p25 expression,
the sequelae of neurodegeneration occur in a rapid and
predictable manner
[25, 26] . In the CK-p25 mouse, p25
overexpression is associated with the eventual death of
nearly 40% of hippocampal and cortical neurons.
HDACi Treatment Reinstates Learning and Restores
Remote Memory after Neurodegeneration
The treatment of 6-week-induced CK-p25 mice, which
display severe neurodegeneration, with the non-selective
HDACi sodium butyrate significantly improves cogni-
tive function
[27] . The HDACis SAHA and phenylbuty-
rate also have the capacity to reinstate learning behavior
in the APPswe/PS1dE9 mouse model of AD
[28, 29] .
HDAC inhibition, which resulted in the recovery of learn-
ing ability, did not affect amyloid pathology itself. Rather,
mice treated with phenylbutyrate displayed elevated H4
acetylation accompanied by an increased production of
proteins implicated in synaptic function
[29] . Therefore,
the use of HDACis has emerged as a promising new strat-
egy for the therapeutic intervention of neurodegenerative
disease
[30 –32] .
Which HDAC is responsible for the cognitive en-
hancement observed following HDACi treatment? To ad-
dress this question, we used a combination of pharmaco-
logical and mouse genetic approaches that allowed us to
identify HDAC2 as a specific negative regulator of synap-
tic plasticity and memory formation
[4] . Chromatin im-
munoprecipitation experiments revealed that HDAC2
associates with the promoters, and likely suppresses the
expression, of a number of genes whose products are im-
plicated in synapse formation/remodeling and memory
formation
[4] . These results suggest that HDACis en-
hance cognitive function by inhibiting HDAC2, render-
ing HDAC2 target genes more accessible to transcription-
al activators and coactivators recruited by neuronal ac-
tivity stimulation. In addition, the impaired cognitive
phenotype of HDAC2-overexpressing mice is readily cor-
rected by SAHA; however, the HDAC2 KO mice are com-
pletely refractory to SAHA treatment. Thus, HDAC2 is
likely to be the major target underlying the beneficial ef-
fects of HDACi treatment. The data presented at the 2011
Barcelona ADPD Conference delineate a novel and im-
portant role for HDAC2 activity in the cognitive impair-
ments associated with neurodegenerative disease.
Conclusion
Our findings delineate an epigenetic mechanism that
underlies memory impairment in neurodegeneration.
These discoveries provide hope for the beneficial effects
of HDAC inhibition. In our model ( fig.1 ), HDAC2 occu-
pancy on the promoters of genes implicated in learning
and memory inhibits the expression of these genes and

The Role of Epigenetic Mechanisms Neurodegenerative Dis
3
leads to cognitive impairment. The recovery of histone
acetylation, via HDAC inhibition, restores histone acety-
lation and the expression of learning and memory and
synaptic plasticity-related genes. The restoration of this
gene expression leads to a reversal of memory deficits.
These data are exciting because they provide hope for
the treatment of neurodegenerative diseases, such as AD,
even when the disease is relatively advanced. Recent clin-
ical trials of pharmacological agents targeting the amy-
loid precursor protein processing pathway in AD have
not provided positive outcomes
[33–37] . One reason giv-
en for this has been that the patients chosen for the trial
were too advanced in their disease, and that these thera-
pies would be most beneficial in people prior to the onset
of AD. However, an estimated 35 million people world-
wide are currently living with dementia, of which AD is
the most common cause
[38 – 4 0] . Should we focus our ef-
forts entirely on preventative or pre-disease stage thera-
peutics and leave these people to their fate? We believe
that a focus upon treatments aimed at ameliorating the
cognitive symptoms and memory loss of dementia, even
when neuronal loss has already occurred, is equally im-
portant in improving the treatment options for people
with neurodegenerative disease. In this realm, therapeu-
tics targeting chromatin remodeling enzymes such as the
HDACs hold great promise.
HDACis facilitate neuronal
activity-induced gene
expression
• Activity-regulated genes: BDNF, c-Fos,
others
• Synaptic remodeling/formation: SVP,
Nrxns, SHANKs, others
• Synaptic plasticity: NR2A/2B,
GluR1/2, CREB, CBP, CaMKII, others
HDACi treatment
X
Color versi on available online
Fig. 1. HDAC2 regulates learning and
memory by suppressing neuronal gene ex-
pression. HDAC2 is present in transcrip-
tional repressor complexes containing
CoREST and is present on the promoters
of activity-regulated genes. HDAC2 ap-
pe ars to be t he mai n tar get of HDAC is t hat
facilitate memory formation by de-re-
pressing HDAC2 target genes. HDACi
treatment can lead to increased histone
acetylation locally, resulting in relaxed
chromatin structure and increased acces-
sibility for transcr iption activation factors,
such as CREB/CBP complexes. The tran-
scriptional activation of CREB/CBP may
further facilitate the expression of neuro-
nal genes functioning in synaptic plastici-
ty, learning and memory, in part through
its associated histone acetyltransferase ac-
tivity. Adapted from Guan et al. [4].
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