 |
 |
|
|
 |
 |
 |
 |
 |
Home » Students » Research Highlights | |
 |
 |
 |
 |
 |
 |
 |
 |
|
Research Highlights From StudentsSignal Transduction Pathology in the Fragile X Nervous SystemMSTP students Dan Kelley and Jamie Elliott collaborated to identify an undiscovered neuropathology in fragile X syndrome, the most common genetic cause of mental retardation and autism. After several exchanges at weekly MSTP seminars and multiple experiments involving four campus laboratories, their findings were published in the Public Library of Science. ---------------- Dan Kelley is an MSTP student in the Neuroscience Training Program, which requires students to propose experiments on a topic unrelated to their primary research area as part of their preliminary examination. Although primarily interested in brain imaging, Dan based his proposed experiments on an interesting paper documenting a molecular phenotype in patients suffering from fragile X syndrome. This work by fragile X researcher Elizabeth Berry-Kravis MD, PhD and colleagues showed that platelets and lymphoblastoid cells of fragile X individuals express unusually low levels of cyclic AMP (cAMP), an intracellular molecule vital to many signaling cascades. Dan wanted to find out if this was also true of fragile X neurons; cAMP is especially important for normal brain function and behavior, and deficient levels of cAMP in neurons could contribute to the pathology of fragile X syndrome. Richard J. Davidson, who is Dan's advisor and Professor of Psychology and Psychiatry and Director of the Waisman Laboratory for Brain Imaging and Behavior, encouraged him to carry out these experiments. Dan did so, measuring cAMP levels in three different models of fragile X syndrome. To test the cAMP theory in human cells, Dan turned to a human neural stem cell line containing the fragile X mutation that had been developed by Anita Bhattacharyya and Clive Svendsen at the Waisman Center. These stem cells were differentiated into brain cells (neurons and glia) that retain the Fragile X mutation. Initial tests of these neural cells conducted in the Waisman Center Stem Cells and Developmental Disorders Laboratory of Anita Bhattacharyya provide evidence that human fragile X brain cells produced less cAMP. These results validated Dan's hypothesis and showed that human brain cells, like human blood cells, have a defect in cAMP signaling and suggest that alteration of the cAMP cascade may be a potential treatment for fragile X syndrome. This work was funded by a grant from FRAXA to Anita Bhattacharyya. To test the cAMP theory in a transgenic mouse model of fragile X, Dan conducted experiments in the laboratory of Garet P. Lahvis, Assistant Professor in the Division of Plastic and Reconstructive Surgery. Findings in mouse cortical tissue mirrored the findings in the human model, with fragile x mice producing less cAMP than wild type mice. To test the cAMP theory in a fragile X fly model, Dan turned to Jerry C.P. Yin, Professor of Genetics and Psychiatry, and Jamie Elliott, an MSTP student in the Genetics program. Dan found that fly heads from a Drosophila model of fragile X also produced less cAMP than controls. Jamie went on to further characterize this finding by examining whether cAMP levels could be returned to normal by reinserting a normal copy of the fmr gene, the gene which is mutated in fragile X patients and in animal models of the disease. To examine whether gene reintroduction had a dose effect Jamie tested Drosophila with either one copy or multiple copies of the fmr1 gene. Jamie found that reintroduction of either one or multiple copies of the fmr1 gene returned cAMP production to normal. The addition of multiple fmr1 copies increased cAMP levels beyond those generated by one additional copy of the gene, although not to statistically significant levels. The results of these basic experiments across multiple models shed further light on the biology of fragile X syndrome and may help to explain the anxiety and memory impairments common in fragile X. They also validate the usage of animal and cell culture models in the study of behavioral disorders such as fragile X syndrome; although it may be difficult or impossible to test behavior in flies or cells, the study of such systems can identify molecular aberrations that may be the key to new therapies. Citation: Kelley DJ, Davidson RJ, Elliott JL, Lahvis GP, Yin JCP, et al. (2007) The Cyclic AMP Cascade Is Altered in the Fragile X Nervous System. PLoS ONE 2(9): e931. doi:10.1371/journal.pone.0000931 Figure 1: Cartoon of cyclic AMP signaling in controls, fragile X (FX), and rescued fragile X (FX+fmr) fly, mouse, and human neural cell models. |
||||
 |
 |
 |
 |
 |
||
 |
||||||