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March 2011

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Dudek explores synaptic plasticity during Council presentation

By Eddy Ball
March 2011

David Miller, Ph.D.

Miller spent about ten minutes reviewing new tenure track appointments, awards to scientists and trainees, and high-profile publications, before introducing Dudek to members of Council. (Photo courtesy of Steve McCaw)

Serena Dudek, Ph.D.

Dudek received the A.E. Bennett Research Award from the Society of Biological Psychiatry for research by a young investigator in 2009 and was granted tenure in October 2010. She was honored during the 2009 Science Awards Day as Mentor of the Year. (Photo courtesy of Steve McCaw)

Continuing the tradition of scientific talks by outstanding researchers at their meetings, on Feb. 17 members of the National Advisory Environmental Health Sciences Council (NAEHSC)(http://www.niehs.nih.gov/about/boards/naehsc/index.cfm) heard about new findings on synaptic plasticity by NIEHS Synaptic and Developmental Plasticity Group Principal Investigator Serena Dudek, Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/ln/sdp/index.cfm)

Following a brief report about the NIEHS Division of Intramural Research, Acting Scientific Director David Miller, Ph.D., introduced Dudek, who spoke on "New Insights into Regulating Synaptic Plasticity: Implications for Autism and Schizophrenia."

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Dudek and her group study synaptic plasticity, the process by which the mammal brain adapts to changes in its internal and external environment, across brain regions and at different stages of development. "We think this is the process that underlies learning and memory in the young and in adults," Dudek said at the beginning of her presentation.

The group's most recent work involves investigating regulation of synaptic plasticity in the CA2 region of the hippocampus. Unlike the adjacent CA1 and CA3 regions, CA2 is a largely uncharted portion of the hippocampus, where Dudek suspects much more can be learned than previously thought about learning as well as the development of social interaction disorders. Growing evidence suggests that the CA2 is important for social behavior and is impaired in cases of bipolar disease and schizophrenia (see text box).

While the formation of the gross structure of the brain, its hardwiring, takes place largely before birth, refinement of the brain's microscopic structure continues well beyond, especially during critical periods of postnatal development when synaptic plasticity is most robust. This refinement also occurs throughout life, as new learning takes place. Environmental exposures during these critical periods, though, have the potential to change the brain's circuitry in potentially harmful ways.

Looking for answers in the CA2

Dudek turned to the CA2 region for her latest experiments, because, she explained, "There's really something fundamentally different about this region." CA2 neurons are highly resistant to most protocols for inducing long-term potentiation (LTP), making the CA2 a fertile ground for discovering molecules that can inhibit synaptic plasticity. For example, in regard to calcium, which is important for plasticity, Dudek found, "The CA2 neurons have almost four times as much of the buffering capacity as do CA1 neurons.... Once we get the calcium up to a comparable level to what's seen in CA1, [however,] we see that the CA2 neurons can express LTP. The CA2 neurons have all the right machinery there."

Dudek has continued to explore the ways calcium is limited in neurons by buffering and extrusion, another of the ways cells deal with calcium. Her group has established that proteins regulating calcium extrusion, such as Pep-19, which is highly enriched in the CA2, can inhibit LTP in CA1 neurons, which normally express robust LTP.

To further explore other molecular players, and to determine the role of CA2 in behavior and learning, Dudek and her collaborators studied mice with a knockout of a CA2-enriched gene, RGS-14. These mice actually had robust plasticity in CA2 and surprisingly, faster memory acquisition. Dudek is currently studying the effects of caffeine and social neuropeptides, which appear to induce LTP in CA2.

Dudek emphasizes, "These are still very new experiments, and we've got a lot of work to do to identify the specific molecular players" and how they function along a veritable labyrinth of pathways. Still, the group plans to continue this line of investigation, because "this is an area of research that could really turn out to be important in brain function," Dudek said.

Dudek, who said she's been interested in the brain since she was in high school, is clearly excited about the possibility of uncovering the mechanisms responsible for regulating synaptic plasticity. She is also seeking to understand what kinds of environmental exposures, such as endocrine disrupting compounds, may impair the normal strengthening and weakening of synapses, and identifying potential targets and interventions for normalizing plasticity in people with autism, schizophrenia, and other psychiatric disorders.

Refinement of the microscopic structure of the brain

In determining its neural circuitry, the mammalian brain undergoes two processes - strengthening synapses or long-term potentiation (LTP) and weakening of synapses known as long-term depression (LTD) and leading to pruning - that are both important in determining how effectively the organism adapts to its environment by shaping brain circuitry in response to experience. Dudek is especially interested in just how these processes are regulated in the brain, which may be especially relevant for understanding developmental brain disorders such as autism and schizophrenia.

"Any gene mutation or environmental toxicant that influences synaptic transmission at all would have the effect of modulating the likelihood of getting LTP or LTD during development," Dudek explained. "We might envision a situation where what we might end up with is abnormal pruning of the brain's circuitry, [which] can have lifelong consequences in cognition."

Referring to autopsy and imaging studies, Dudek noted that a thickening of the cerebral cortex has been observed in the brains of people with autism, possibly due to less than normal pruning of synapses, while a greater than normal pruning of synapses has been found in schizophrenics.

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