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News from the Society for Neuroscience Annual Meeting: Researchers Identify Epigenetic Key to Strengthening Memory in Aging Brains

Talan, Jamie

doi: 10.1097/01.NT.0000475376.48403.46
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ARTICLE IN BRIEF

Researchers reported at the Society for Neuroscience annual meeting that by depleting histone deacetylase 3 from the dorsal hippocampus in aging mice, they were able to enhance memory and long-term potentiation.

CHICAGO—A change in a single enzyme, histone deacetylase 3 or HDAC3, was powerful enough to help strengthen memory in an older animal, according to a study conducted by scientists at the University of California, Irvine (UCI).

The strategy — to disrupt gene expression of HDAC3 — was described here in October at the Society for Neuroscience annual meeting.

Janine L. Kwapis, PhD, a postdoctoral researcher in the lab of Marcelo A. Wood, PhD, at UCI, and her colleagues discovered that HDAC3 was a key enzyme responsible for removing acetyl groups from histones, proteins that are wrapped around DNA. This deacetylation keeps DNA tightly bound, and the addition of a histone group allows gene expression to occur.

She believes that this may be a key factor in explaining what is happening in the aging brain. In the brain, HDAC3-mediated deacetylation works like a molecular brake pad, restricting gene expression until a learning event occurs. When learning happens, HDAC3 is inhibited and acetyl groups are added, paving the way for gene expression. But DNA requires a flexible system, and there may be disruptions in this system as the brain ages.

“We know that gene expression is disrupted when you get older,” said Dr. Kwapis. “We are trying to figure out why it happens and how to correct it. Our DNA is not just sitting there, but is compacted. An environmental event will interact with that gene and change its expression. We are looking at a single epigenetic mechanism, the addition or deletion of an acetyl group from a histone. Acetylation allows gene expression to occur.”

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STUDY METHODOLOGY

Dr. Kwapis completely depleted the HDAC3 protein from the dorsal hippocampus in mice and observed that the older mice were learning tasks — and not forgetting them — as if they were younger. The task involved introducing animals to an object in a particular environment. The animals were then brought back the next day. By moving the object to a different location, the researchers were able to measure what the animals had learned the day before. Young mice learn this task easily; older mice normally have a harder time, Dr. Kwapis said.

Depleting HDAC3 in the older animals enhanced memory, and there was also a change in a critical cellular component of synaptic plasticity and long-term potentiation (LTP), a measure of how well neurons communicate with each other.

“We restored long-term potentiation in these older mice,” said Dr. Kwapis.

The researchers also looked at the expression of three genes known to be associated with learning — cFos, Arc, and Nr4a2 — to see if there were any differences in the expression of these genes in younger and older animals and in the animals with depleted HDAC3.

Dr. Kwapis reported at the meeting that only the Nr4a2 expression was changed in older brains of animals without HDAC3. “This makes us believe that Nr4a2 is critical to aging, and expressing it in the aging brain may be enough to strengthen learning. It suggests that maybe we can disrupt HDAC3 and restore a more normal epigenetic state to prolong normal cognition in old age.”

The scientists are now working with pharmaceutical companies to identify compounds that selectively block HDAC3. “There is a strong push now to develop small molecule inhibitors that selectively block HDAC3,” said Dr. Wood, professor and chair of the department of neurobiology and behavior at UCI.

“Selective inhibitors will allow us to manipulate specific epigenetic mechanisms in the brain in a safer way, bringing us that much closer to the development of real novel therapeutic approaches,” he said.

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EXPERTS COMMENT

“This group is at the forefront of work on epigenetics and memory,” said Fred Helmstetter, PhD, a professor in the department of psychology at the University of Wisconsin-Milwaukee. “There is growing evidence of changes in chromatin structure regulation being important for age-related memory impairment. The specific idea from Dr. Kwapis and her colleagues that HDAC3 dysregulation contributes to cognitive dysfunction in aging, combined with their data using targeted genetic disruption of the molecule (as opposed to less specific pharmacological inhibitors, for example), seems like a big step forward in this area. This line of work will be important.”

“As molecular behavioral scientists, we are constantly in search of ways to improve cognitive function, including memory formation and retention in the elderly,” said Farah Lubin, PhD, an assistant professor in the department of neurobiology at the University of Alabama at Birmingham. “Dr. Wood's work adds yet another promising avenue for therapeutic treatment options for reversing memory deficits with normal aging. Specifically, epigenetic mechanisms such as regulation of HDAC activity represent an innovative locus that can be targeted to influence the process of memory storage with age. By increasing our knowledge of these types of molecular processes, we are closer to developing therapeutic interventions and possibly a cure for age-related dementias like Alzheimer's disease.”

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EXPERTS: ON AN EPIGENETIC KEY TO STRENGTHENING MEMORY

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LINK UP FOR MORE INFORMATION:

•. Society for Neuroscience abstract: Kwapis JL, Alaghband Y, Kramar EA, et al. Memory consolidation and reconsolidation: Molecular mechanisms. http://bit.ly/NT-HDAC3-SfN
•. Bieszczad KM, Bechay K, Rusche JR, et al. Histone deacetylase inhibition via RGFP966 releases the brakes on sensory cortical plasticity and the specificity of memory formation http://www.jneurosci.org/content/35/38/13124.abstract. J Neurosci 2015; 35(38): 13124–13132.
•. Lattal KM, Wood MA. Epigenetics and persistent memory: Implications for reconsolidation and silent extinction beyond the zero http://www.nature.com/neuro/journal/v16/n2/full/nn.3302.html. Nat Neurosci 2013;16(2):124–129.
•. Kwapis JL, et al. Does PKM(zeta) maintain memory http://www.sciencedirect.com/science/article/pii/S0361923013001445. Brain Res Bull 2014; 105:36–45.
© 2015 American Academy of Neurology