University at Buffalo - The State University of New York

Published: October 6, 2005

By LOIS BAKER
Contributing Editor

Neuroscientists at UB have shown in two recently published papers that destabilization of structures called microtubules—intracellular highways that transport receptors to their working sites in the brain—likely underlie many mental disorders and could be promising targets for intervention.

This image shows the cryo-EM structure of a microtubule.

In their most recent article, published last month in the Journal of Biological Chemistry, they report that destabilization of microtubules interferes with the action of the NMDA receptor, a target of the neurotransmitter glutamate, which plays a critical role in learning and memory.

"You can think of NMDAR as the cargo moving along a railway consisting of the microtubules cytoskeleton," said lead author Eunice Yuen, graduate student in the laboratory of Zhen Yan, associate professor in the Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences.

"Microtubules are hollow cylinders made up of polymers of the protein tubulin," she said. "Agents that break up, or depolymerize, microtubules disrupt the railway, stop the traffic and reduce the number of cargoes that get delivered to the neuronal surface.

"In turn, fewer NMDA receptors are available on the surface of the neuron to interact with its neurotransmitter, which results in fewer signals being transmitted to critical areas of the brain," said Yuen. "Defects in neuronal transport are involved in many neurological diseases."

In an earlier paper from Yan's group published in June in the Journal of Neuroscience, the researchers showed that the neuromodulator serotonin, crucial to the treatment of depression and anxiety, also regulates NMDA receptor function through the mechanism dependent on microtubules. Yan was senior author on both papers.

"We hypothesize that the function of the serotonin receptor known as 5-HT1AR is to suppress the activity of the NMDA receptor by coupling to cellular signaling, which depolymerizes microtubules," said Yuen, first author on the paper. "The breakup of microtubules, in turn, interrupts NMDAR delivery to the neuronal surface, resulting in suppression of NMDAR function.

"This evidence shows that serotonin can regulate NMDAR transport along the microtubule cytoskeleton in neurons," she said. "Dysfunction of this regulation may provide a potential mechanism underlying many mental disorders."

Also contributing to these studies were Zhenglin Gu, postdoctoral associate; Paul Chen, medical and doctoral student in Yan's laboratory; and Qian Jiang, postdoctoral associate in the laboratory of Jian Feng, associate professor of physiology and biophysics.

The studies were supported by grants from the National Institutes of Health and the National Science Foundation, and a National Alliance for Research on Schizophrenia and Depression Independent Investigator Award to Yan.k