The fine art of brain development  pg. 7

Because FMRP is a protein that regulates the expression of other proteins, Broadie and his colleagues are looking for genes and proteins that might be affected by FMRP.

Only a handful—about eight—have been proven so far. One protein found by the Broadie team regulates the internal scaffolding, or cytoskeleton, of neurons, which, he says, “makes perfect sense in that the main defect you see is the change in the structure of nerve cells (and) the cytoskeleton determines the structure.”

Another prospect is the involvement of a neurotransmitter receptor called the metabotropic glutamate receptor (mGluR). The receptor—which is activated by glutamate, the main excitatory neurotransmitter in the central nervous system— is important for neuronal plasticity throughout life, and FMRP acts downstream of mGluR activity. Broadie is using the fly model to study the interactions between mGluR and FMRP by manipulating the expression of their corresponding genes in combination.

Studies in mice suggest that excessive signaling through mGluR5 may be responsible for the neurological and psychiatric consequences of fragile X syndrome. Even though FMRP is missing in humans with fragile X, Broadie notes, it may be possible to find ways to manipulate signaling through the mGluR and circumvent some of the later problems of fragile X.

Researchers at Vanderbilt, for example, have identified more than 400 “negative allosteric modulators,” compounds that selectively “turn down” the activation of mGluR when glutamate binds to it. With support from Seaside Therapeutics of Cambridge, Mass., they are developing compounds with drug-like properties for further study.

“It's a really innovative idea,” says Jeffrey Conn, Ph.D., director of the Vanderbilt Program in Drug Discovery, who is leading the project in collaboration with Craig Lindsley, Ph.D., Alice Rodriguez, Ph.D., and David Weaver, Ph.D. “If it works, it could be transformative … It could totally change the way people view developmental disorders.”

Unlike sculpture released from stone by the human hand, the brain never achieves a final form. The biological “thinker” is constantly in motion. Throughout life, synapses rearrange and become stronger or weaker, neurons die and (in a few cases) new neurons are born.

Though invisible to the naked eye, this dynamic, continual process of brain sculpting is what gives brain researchers hope that we can find ways to not only treat or prevent diseases like fragile X, but also to just improve the function of the normal brain.

“The brain is not static, it constantly changes itself in response to its environment,” says Broadie. “Your heart doesn’t do that. Your liver doesn’t do that. That’s the property that makes it so special.

“That’s what makes the brain, the brain.”

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