A pinboard by
Philipp Mews

Postdoctoral Fellow, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai


Epigenetics: key to laying down spatial memories, providing possible new neurological medications

Understanding how memories are made, retrieved, and eventually fade over a lifetime is the stuff of poems and song. To medical researchers, solving the mysteries of memory is even more elusive. Researchers surmise that “laying down” a new memory and storing an old memory both involve making proteins at the space, or synapse, where one neuron meets another. But forming these also requires new gene expression in the cell nucleus, where DNA is stored and genes are “read” to establish cell-specific functions. In my work, I discovered that a key metabolic enzyme works directly within the nucleus of neurons to turn genes on or off when new memories are being established. This enzyme, called acetyl-CoA synthetase 2, or ACSS2, ‘fuels' a whole machinery of gene expression ‘on site’ in the nucleus of nerve cells to turn on key memory genes after learning. This discovery provides a new target for neuropsychiatric disorders, such as anxiety and depression, where neuro-epigenetic mechanisms are known to play key roles. How are memories stored in the brain? Forming memories involves a restructuring of the synapse, which relies on the coordinated expression of a group of memory genes. The addition of a chemical group, a process called acetylation, onto specific spots of the genome in neurons, opens up tightly-wound DNA. This allows genes involved in memory formation to be “read,” and eventually, for their encoded proteins to be made. Such epigenetic mechanisms are becoming better understood as important regulators of the many functions of neurons. And we discovered a new key player: the enzyme ACSS2 binds to memory genes directly to fuel their acetylation, which is ultimately controlling spatial memory in mice. ACSS2 ‘fuels’ the memory machine? We found that if the animals’ ACSS2 expression was blocked, long-term memory of where objects were placed in a study chamber was impaired. These mice did not investigate a moved object on the second day of a two-day trial, while control group mice did. This is because without ACSS2, the mice had no molecular path to engage memory genes to lock in where the objects were placed. In turn, this decrease in ACSS2 in specific brain regions impairs the read-out of key genes that function to form new memories or to update old ones. In the future, we hope to apply this newfound memory path to prevent the “laying-down” of traumatic memories -- or perhaps even erase them -- in people who suffer from post-traumatic stress disorder.


Epigenetic regulation of memory formation and maintenance.

Abstract: Understanding the cellular and molecular mechanisms underlying the formation and maintenance of memories is a central goal of the neuroscience community. It is well regarded that an organism's ability to lastingly adapt its behavior in response to a transient environmental stimulus relies on the central nervous system's capability for structural and functional plasticity. This plasticity is dependent on a well-regulated program of neurotransmitter release, post-synaptic receptor activation, intracellular signaling cascades, gene transcription, and subsequent protein synthesis. In the last decade, epigenetic markers like DNA methylation and post-translational modifications of histone tails have emerged as important regulators of the memory process. Their ability to regulate gene transcription dynamically in response to neuronal activation supports the consolidation of long-term memory. Furthermore, the persistent and self-propagating nature of these mechanisms, particularly DNA methylation, suggests a molecular mechanism for memory maintenance. In this review, we will examine the evidence that supports a role of epigenetic mechanisms in learning and memory. In doing so, we hope to emphasize (1) the widespread involvement of these mechanisms across different behavioral paradigms and distinct brain regions, (2) the temporal and genetic specificity of these mechanisms in response to upstream signaling cascades, and (3) the functional outcome these mechanisms may have on structural and functional plasticity. Finally, we consider the future directions of neuroepigenetic research as it relates to neuronal storage of information.

Pub.: 17 Jan '13, Pinned: 10 Oct '17