2 min readNew Pathway Regulates Information Processing in The Brain

Neuroscientist Anton Maximov (right), graduate student Richard Sando III and colleagues are shedding light on the biology of learning and memory.

La Jolla, CA – 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, and found that imbalances in this pathway could contribute to cognitive abnormalities in humans.

The research focused on the actions of a protein called HDAC4 and they found that it 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 this study.

Searching for Missing Pieces

Synapses (the specialized junctions that allow neurons to exchange information) are incredibly complex and built with hundreds of genes. Many of these genes become induced when neurons receive excitatory input from other neurons, including those activated by sensory experiences such as vision, hearing and smell. This process influences the assembly of neural circuits during development, and plays a fundamental role in learning and memory.

The research team was interested in understanding how synapses are formed and regulated. According to their press report, previous studies have identified several factors necessary for activity-dependent transcription in the brain (a process of converting genetic information from DNA to RNA). However, Maximov highlighted that many puzzles remain to be solved. For example, the majority of synapse-related genes are silent in the embryonic brain, which does not receive direct sensory input from an external world. These genes become de-repressed shortly after birth, yet scientists still know little about the underlying mechanisms of how this happens.

The researchers said that they become interested in class IIa histone deacetylases (HDACs), which include HDAC4, in part because they have been implicated in regulation of transcription of non-neuronal tissues. “Class IIa HDACs are also known to change their cellular localization in response to various signals,” explained Richard Sando III, member of the Maximov lab and the first author of this study. “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.”

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 obstacle – HDAC4 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 generated mice carrying a mutant form of HDAC4 that could not be exported from the cell nucleus. This mutant 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. “One of these human mutations produces a protein similar to a mutant that we introduced into the mouse brain,” said Maximov. “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.”

The research is published in the November 9, 2012 issue of the journal Cell.

Leave a Reply

© Mindzilla. All rights reserved.