Scripps Scientists Uncover a New Pathway that Regulates Information Processing in the Brain
Scientists at The Scripps Research Institute (TSRI) have identified a new pathway that appears to play a major role in information processing in the brain. Their research also offers insight into how imbalances in this pathway could contribute to cognitive abnormalities in humans
The study focuses on the actions of a protein called HDAC4 which researchers found is critically involved in regulating genes essential for communication between neurons. “We found that HDAC4 represses these genes, and its function in a given neuron is controlled by activity of other neurons forming a circuit,” said TSRI Assistant Professor Anton Maximov, senior investigator for the study.
The work is published in the November 9, 2012 issue of the journal Cell.
Searching for Missing Pieces
Synapses are junctions between genes that are
specialized to allow neurons to exchange information,
are incredibly complex and built with hundreds of genes.
Many of these genes become functional when neurons
receive excited input from other neurons, including
those activated by sensory input such as vision,
hearing and smell. These processes influence
the assembly of neural circuits during
fetal development, and play a
fundamental role in
learning and memory.
The Maximov laboratory is interested in understanding how synapses are formed and regulated. Previous studies have identified several factors needed in the brain for activity-dependent transcription (the process that converts genetic information from DNA to RNA).
However, Maximov notes many puzzles remain to be solved. For example, the majority of synapse-related genes are silent (turned off) in the embryonic brain, as an embryo doesn't receive direct sensory input from our external world. These silent genes become de-repressed or active shortly after birth, yet scientists still know little about the underlying mechanisms of how this happens.
Richard Sando III, a graduate student at the TSRI Kellogg School of Science and Technology, a member of the Maximov lab and the first author of this study, noted the team became interested in class IIa histone deacetylases (HDACs), which includes HDAC4, in part because both molecules had been implicated in regulation of transcription of non-neuronal tissues.
Sando:“Class IIa HDACs are also known to change their cellular localization in response to various signals. There were hints that, in neurons, the translocation of HDAC4 from the nucleus to cytoplasm may be triggered by synaptic activity. We found that mutant mice lacking excitatory transmitter release in the brain accumulate HDAC4 in neuronal nuclei. But what was really exciting was our discovery that nuclear HDAC4 represses a pool of genes involved in synaptic communication and memory formation.”
Coincidentally, Maximov had been familiar with these same genes since his postdoctoral training with Tomas Sudhof, a neuroscientist whose pioneering work resulted in the identification of key elements of the transmitter release machinery. “It was truly astonishing when their names came up in our in vitro genome-wide mRNA profiling screens for neuronal HDAC4 targets,” Maximov said.
A Link to a Rare Human Disease
To learn more about the function of HDAC4 in the brain, the team wanted to study its role in a mouse model. First, however, the scientists had to overcome a serious technical obstacleHDAC4 also appears to protect neurons from apoptosis (programmed cell death), so complete inactivation of this gene would lead to neurodegeneration. To solve this problem, the team created mice that carry a mutant form of HDAC4 which cannot be exported from the cell nucleus. This mutant mouse repressed transcription independently of neuronal activity.
Another surprise came after the team had already
initiated their experiments. Underscoring the team’s
findings, a human genetic study was published linking
mutations in the human HDAC4 locus with a rare
form of mental retardation.
Maximov: “One of these human mutations
produces a protein similar to a mutant that we
introduced into the mouse brain. Furthermore,
our studies revealed that these mice do not learn
and remember as well as normal mice, and their
memory loss is associated with deficits in synaptic
transmission. The pieces came together.”
Most of the work in the new study was performed at TSRI’s Dorris Neuroscience Center, which has state-of-the-art imaging, molecular biology and animal facilities. “Here at the DNC we enjoy a terrific research environment,” Maximov said. “It would have been very difficult if not impossible for us to successfully perform these studies without the support of Helen Dorris and our senior colleagues who have assembled a highly productive and collaborative group of molecular neuroscientists.”
Other contributors to the study, “HDAC4 Governs a Transcriptional Program Essential for Synaptic Plasticity and Memory,” were Natalia Gounko and Simon Pieraut from the Maximov Laboratory; John Yates III, professor in the Department of Chemical Physiology at TSRI; and Lujian Liao, a staff scientist in the Yates Laboratory.
The research was funded in part by National Institutes of Health grants MH085776, MH067880-09, RR011823, and NS057096, and by the Novartis Advanced Discovery Institute, The Baxter Foundation and the Helen Dorris Postdoctoral Fellowship.
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. Over the past decades, TSRI has developed a lengthy track record of major contributions to science and health, including laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. The institute employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientistsincluding three Nobel laureateswork toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.
Original article: http://www.scripps.edu/news/press/2012/20121109maximov.html