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Environmental Factor, March 2014

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NIEHS researcher wins grant to study IGF1 receptor and hippocampal plasticity

By Kelly Lenox

Serena Dudek, Ph.D.

“We’re excited at the possibility that the grant will raise the visibility of CA2 research among those interested in autism and other developmental disorders. I’m a strong believer in basic research and am excited about the opportunity to research Rett syndrome, which we wouldn’t have without this grant.” (Photo courtesy of Steve McCaw)

The International Rett Syndrome Foundation, in January, awarded a 2-year, $98,000 grant to NIEHS researcher Serena Dudek, Ph.D., to study the role of insulin-like growth factor 1 (IGF-1) receptor in hippocampal CA2 plasticity and function.

IGF-1 has shown promise for treatment of Rett syndrome (RTT), a serious and poorly understood neurological disorder (see sidebar). Dudek, noting that the primary receptor for this growth factor is highly expressed in the CA2 region of the hippocampus, proposes that novel insights into the nature of RTT may be gained by studying the effects of IGF-1 signaling in CA2 pyramidal neurons.

Dudek heads the NIEHS Synaptic and Developmental Plasticity Group in the Laboratory of Neurobiology. By studying factors affecting development and function of the brain’s synapses, the group pursues deeper understanding of how environmental factors affect the circuitry of the brain. Her group is one of a very few labs, worldwide, investigating synaptic plasticity in the CA2 area, and one of a handful at NIEHS successfully applying for outside support to pursue its studies (see text box).

Unique opportunity

Dudek’s lab previously found that, although the hippocampus is known for its synaptic plasticity, the CA2 area, in particular, is not very plastic. In fact, the CA2 differs from other hippocampal areas in a number of structural, molecular, and physiological ways. One of those differences is that the IGF-1 receptor is more highly expressed in CA2 than almost anywhere else in the brain.

“Since we have expertise in CA2 physiology, where the receptor is highest, it seemed like an opportunity not to pass up,” Dudek said. “Our work will provide insight into how IGF-1, which is currently undergoing clinical trials, is acting on CA2 neuron function.” The results of the study may shed light on the outcome of the clinical trials and be crucial for developing the next generation of drugs.

RTT and the hippocampus

RTT is associated with a mutation in the MeCP2 gene, located on the X chromosome. Other researchers have shown that mice bred to be deficient in the MeCP2 gene have smaller CA2 neurons. Research funded by this grant will determine whether, when treated with IGF-1, the impact on the anatomy or physiology of CA2 pyramidal neurons is different from the impact on other hippocampal or cortical neurons, in both wild type and MeCP2-mutant mice.

Dudek’s team previously found that synaptic potentiation in CA2 could be pharmacologically induced with agents, including caffeine and the social neuropeptides vasopressin and oxytocin, at concentrations that had little effect in other regions of the hippocampus. That finding, combined with other studies implicating the hippocampus in social behavior in rodents, led her team to hypothesize that CA2 is the social module of the hippocampus. The new study is designed to determine whether CA2 is implicated as a critical module of cognitive processes affected by RTT.

Growing ranks of NIEHS awardees

According to William Schrader, Ph.D., deputy scientific director of the NIEHS Division of Intramural Research, about one NIEHS scientist a year is awarded a grant from an external source, though many more apply. As Schrader explained, “There are not a lot of grants for which NIEHS intramural scientists are eligible to apply. Dudek is a good example of an investigator who found that her work was directly on point with a grant opportunity and took advantage of it.”

NIH is working to increase successful applications among staff of all the institutes, according to Darryl Zeldin, NIEHS scientific director (SD) and head of the Environmental Cardiopulmonary Disease Group in the Laboratory of Respiratory Biology. “Michael Gottesman [M.D.] in Bethesda, the deputy director for all intramural research programs, is compiling, for all SDs, a list of organizations whose funds NIH is eligible to apply for, and where we have been successful, so that SDs can encourage scientists to apply,” said Zeldin.

In addition to easing the burden of tight funding, such grants raise visibility for the work of NIEHS scientists. “Dudek’s grant is a great example of a small organization that doesn’t give a lot of money out, but if you get a competitive proposal from a top researcher like Serena you can be successful,” Zeldin continued. “All of these smaller organizations do publicity around which researchers get grant money and what they’re studying, so it’s very good visibility for NIEHS.”

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