Re-opening the Memory Book

Following the completion of the Human Genome Project, much of biology’s focus has been shifted from the raw sequence of genes to their regulation over time and in response to environmental stimuli. Like books on a shelf, genes do not exert effects by their mere presence; rather, the pages of the book (i.e., the chromatin) need to be opened so that the words (i.e., the genes) can be read and interpreted correctly. The epigenetic regulation of gene expression refers precisely to this process.

In 1984, Francis Crick (1916-2004) proposed that memory might be coded in alterations to particular stretches of chromosomal DNA. Although the response to this idea was relatively modest at the time, the past decade has shown that chromatin, the carrier of chromosomal DNA, undergoes dynamic modifications and conformational changes during memory formation. One of these modifications is histone acetylation, the addition of an acetyl group to histone proteins. Histone acetylation is regulated by the opposing activities of histone acetyltransferases and histone deacetylases (HDACs) and generally closely correlates with active gene expression. Rodents display a transient increase in histone acetylation after exposure to various learning paradigms, and synaptic plasticity and memory formation are facilitated after treatment with small molecule inhibitors of HDACs.

Alzheimer’s disease (AD) erodes learning and memory and other cognitive functions and is one of the most devastating diseases facing modern society. AD is the leading cause for senile dementia and affects more than five million people in this country. The mechanisms underlying the pathophysiology of AD remain to be elucidated and there is currently no medication that can prevent, reverse, or cure the disease. Using a powerful mouse model of AD that exhibits profound neuronal loss, memory deficits, and other AD-like pathologies, we made the unexpected finding that HDAC inhibitor administration markedly reinstalled the synaptic plasticity and learning behavior of the mice. Moreover, the same treatment also facilitated the recovery of seemingly lost memories that were acquired prior to neurodegeneration. These observations suggest that chromatin remodeling facilitated by small molecule HDAC inhibitors is beneficial for cognitive function – even after such function has been impaired following Alzheimer’s like neurodegeneration.

Encouraged by the data, we became interested in further deciphering the mechanism by which inhibition of the HDACs is beneficial for cognition. Using a combination of pharmacological and mouse genetic approaches, we identified histone deacetylase 2 (HDAC2) as playing a master role in regulating the expression of genes participating in synaptic plasticity and memory formation. HDAC2 binds to the promoter of a plethora of these genes, including but not limited to Arc, Egr1, synaptophysin, NMDA receptor subunits, AMPA receptor subunits, CREB, and BDNF, and negatively influences their expression. These results were consistent with a contemporary publication demonstrating that HDAC2 became posttranslationally modified after neuronal activity stimulation, which in turn led to its dissociation from the chromatin and permitted the expression of CREB-dependent gene expression. Importantly, a mouse model with increased HDAC2 level in the brain exhibited impaired learning and memory, whereas animals with reduced HDAC2 level showed enhanced synaptic plasticity and learning capacities. Finally, while wild-type rodents responded to HDAC inhibitor treatment with facilitated learning behavior, HDAC2 loss of function mice were refractory to enhanced cognition mediated by HDAC inhibitor treatment. These results prompted us to propose that HDAC2 controls the expression of learning and memory genes by regulating the acetylation of nearby histones and the accessibility of these genes to transcriptional activators (Figure i). Also, HDAC2 appears to be the main target of chemical HDAC inhibitors beneficial for cognition.

"A gene therapy approach that reduced HDAC2 level in neurons of an AD [Alzheimer’s Disease] mouse model not only restored expression of memory genes, but also ameliorated synaptic plasticity and cognitive defects."
Currently, we are investigating how altered chromatin remodeling contributes to various symptoms of AD. Johannes Gräff, a postdoctoral associate in the lab, found that the expression of HDAC2 itself is sensitive to adverse environmental contingencies. In neurons, ß-amyloid peptides, considered the chief culprit of AD, and oxidative stress, widely considered to contribute to neurodegeneration, caused increased expression of HDAC2 via mechanisms involving the activation of glucocorticoid receptor 1, a stress hormone receptor. The elevated level of HDAC2 in turn, led to more pronounced association of HDAC2 with memory genes and permanent inhibition of their expression. Several lines of evidence indicate that the epigenetic blockade of memory gene expression mediated by elevated HDAC2 is pertinent to AD. First, the elevated HDAC2 level was observed not only in neurons of two different AD mouse models, but also in human postmortem AD brains (Figure ii). Moreover, a gene therapy approach that reduced HDAC2 level in neurons of an AD mouse model not only restored the expression of memory genes, but also ameliorated synaptic plasticity and cognitive deficits. This beneficial effect of HDAC2 reduction occurred despite persistent neuronal loss, suggesting that neurons even within a severely neurodegenerated brain have not completely lost their transcriptional and synaptic plasticity; rather, that such plasticity has been constrained by an HDAC2-mediated epigenetic blockade.

Interestingly, in an independent study, HDAC2 was also shown to be elevated in aging rodent brains and responsible for cognitive aging. Together, these data reveal for the first time that the epigenetic landscape is drastically altered in aging and AD so that genes necessary to maintain cognitive function are no longer accessible for normal transcriptional regulation. Crucially, however, these results also suggest that cognitive decline associated with AD and aging might be reversible by unlocking this blockade of gene transcription (Figure i).

Supported by the Bard Richmond Fund, Gräff is currently using selective HDAC2 chemical inhibitors to counteract cognitive decline and other AD associated pathologies in mouse models. Research from other fields has demonstrated that pathological epigenetic modifications are readily amenable to pharmacological interventions and have therefore raised justified hopes that the epigenetic machinery provides a powerful new platform for therapeutic approaches against cognitive decline caused by aging and AD.

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