Microtubules Critical To Development Of Mental Disorders

Intheir most recent article, published in the Aug. 19 issue of theJournal of Biological Chemistry, they report that destabilization ofmicrotubules interferes with the action of the NMDA receptor, a targetof the neurotransmitter glutamate, which plays a critical role inlearning and memory.

"You can think of NMDAR as the cargo movingalong a railway consisting of the microtubules cytoskeleton," said leadauthor Eunice Yuen, graduate student in the laboratory of Zhen Yan,Ph.D., associate professor in the Department of Physiology andBiophysics, UB School of Medicine and Biomedical Sciences.

"Microtubulesare hollow cylinders made up of polymers of the protein tubulin," shesaid. "Agents that break up, or depolymerize, microtubules disrupt therailway, stop the traffic and reduce the number of cargoes that getdelivered to the neuronal surface.

"In turn, fewer NMDA receptorsare available on the surface of the neuron to interact with itsneurotransmitter, which results in fewer signals being transmitted tocritical areas of the brain," said Yuen. "Defects in neuronal transportare involved in many neurological diseases."

In an earlier paperfrom Yan's group published in the June 8 issue of the Journal ofNeuroscience, the researchers showed that the neuromodulator serotonin,crucial to the treatment of depression and anxiety, also regulates NMDAreceptor function through the mechanism dependent on microtubules. Yanwas senior author on both papers.

"We hypothesize that thefunction of the serotonin receptor known as 5-HT1AR is to suppress theactivity of the NMDA receptor by coupling to cellular signaling, whichdepolymerizes microtubules,"

said Yuen, first author on thepaper. "The breakup of microtubules, in turn, interrupts NMDAR deliveryto the neuronal surface, resulting in suppression of NMDAR function.

"Thisevidence shows that serotonin can regulate NMDAR transport along themicrotubule cytoskeleton in neurons," she said. "Dysfunction of thisregulation may provide a potential mechanism underlying many mentaldisorders."

Also contributing to these studies were Zhenglin Gu,post-doctoral associate, and Paul Chen, medical and doctoral student inYan's laboratory, and Qian Jiang, post-doctoral associate in thelaboratory of Jian Feng, Ph.D., UB associate professor of physiologyand biophysics.

The studies were supported by grants from theNational Institutes of Health and the National Science Foundation, anda National Alliance for Research on Schizophrenia and DepressionIndependent Investigator Award to Yan.

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