Study Focuses on Brain Receptor Involved in Cognitive Disorders

BUFFALO, N.Y. -- Only one drug is approved to treat persons with mild to moderate Alzheimer's symptoms, despite the fact that the brain protein at the core of this disease, the NMDA receptor, is known to play a central role in several acute and chronic neurodegenerative conditions that impair learning and memory.

Gabriela Popescu, Ph.D., assistant professor of biochemistry at the University at Buffalo's School of Medicine and Biomedical Sciences, is hoping to help change that situation.

She is beginning a new study, funded by the National Institutes of Health, to investigate the mechanisms that control these receptors, and to learn how to disrupt certain damaging NMDA receptor functions, while leaving its other important functions intact.

"Understanding how NMDA receptors work will help neuroscientists address, rationally, neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's, and may provide novel therapies for stroke and schizophrenia," said Popescu, a member of the Neurodegenerative Group in the New York State Center of Excellence in Bioinformatics and Life Sciences at UB.

"The shortage of useful therapies is particularly frustrating, given the many distinct regulatory sites available on the NMDA receptor. We are very hopeful we can address this urgent need for a better understanding of how NMDA receptor activities are, or can be, controlled."

Her research is funded by a $1.6 million grant from the National Institute of Neurological Disorders and Stroke.

The NMDA receptor and its neurotransmitter glutamate have been the focus of intense neuroscience research in recent years.

"Ninety percent of all excitatory neuronal signaling in the brain is controlled by glutamate, and half of it requires NMDA receptors," Popescu said. "We need these proteins for the correct wiring of our brains and throughout life to form and retain memories, to learn new skills and behaviors. We cannot function properly without them.

"Underactivity of NMDA receptors may be a cause of schizophrenia, while overly active NMDA receptors kill neurons, causing devastating brain damage following a stroke," she said. "NMDA receptors also are involved with pernicious illnesses such as Alzheimer's, Parkinson's and Huntington's in ways that are not yet clear."

Popescu was lead researcher on a study, published in Nature in 2004, that described for the first time how these receptors can act as "frequency discriminators," with the potential capacity to determine whether a neuron will learn to become more or less receptive to future experiences.

Her follow-up article in Molecular Pharmacology showed it should be possible to find drugs that regulate certain NMDA receptor functions, while leaving others alone.

"In addition to proving this important principle," said Popescu, "we anticipate that the NIH project also will suggest novel strategies, perhaps combinatorial, to control specifically the receptor properties responsible for pathologic states, while preserving its required functions in synaptic transmission and plasticity.

"A better understanding of how these proteins work holds great hope for addressing neurodegenerative diseases in the future."

The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York. The School of Medicine and Biomedical Sciences is one of five schools that constitute UB's Academic Health Center.