NMDA Receptors Function as 'Frequency Discriminators,' Possibly Initiating Long-Term Potentiation or Depression of Synapses, Biophysicists Find

BUFFALO, N.Y. -- The NMDA receptor, a brain protein crucial for learning and memory, can function as a "frequency discriminator," translating stimulation frequency into current amplitude and possibly deciding whether the neuron will learn to become more or less receptive to future experiences, University of Buffalo biophysicists have revealed.

The researchers were able to uncover this phenomenon using cutting-edge techniques that allow them to monitor one receptor at a time, and by employing advanced computer software developed at UB, to analyze the complex behavior of individual proteins.

Results of their original work appear in the August 12 issue of Nature.

Understanding how NMDA receptors work will help neuroscientists learn more about neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's, and may provide novel therapies for stroke and schizophrenia, said Gabriela Popescu, Ph.D., research assistant professor of anesthesiology and physiology and biophysics affiliated with UB's Center for Single Molecule Biophysics and lead author of the work.

"At most synapses, both long-term potentiation (LTP) and long-term depression (LTD) require the activation of NMDA receptors," she said. "Unfortunately, these receptors exhibit notoriously complex behaviors and have resisted the solution of their activation mechanism for more than 10 years.

"In our past work we were able to make some headway in understanding the pathway by which these receptors become active. Our current research gives us confidence that we are on the right track."

NMDA receptors, which respond to the neurotransmitter glutamate, have been the focus of intense neuroscience research for good reason, Popescu said. "Ninety percent of all excitatory neuronal signaling is mediated by glutamate, and half of it occurs through NMDA receptors. 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 live without them."

Underactivity of NMDA receptors may be the cause of schizophrenia, while overly active NMDA receptors kill neurons, causing devastating brain damage following a stroke. NMDA receptors also are involved with pernicious illnesses such as Alzheimer's, Parkinson's and Huntington's, and a better understanding of how these proteins work holds great hope for addressing these diseases.

Of particular importance to the function of these receptors, and often to their malfunction, is the pathway by which these molecules change shape after binding the neurotransmitter glutamate to allow ions to rush into the postsynaptic neuron and send the signal onward. Popescu and colleagues Anthony Auerbach, Ph.D., professor of physiology and biophysics in the UB Center for Single Molecule Biophysics, along with Antoine Robert, M.D., Ph.D., and James R. Howe, Ph.D., of the Yale University School of Medicine, report in Nature that only about half of the pool of receptors bombarded with glutamate is recruited to respond by each stimulus, while the remaining half stays ready to take "orders" from the next signal.

"The interplay between how fast the receptor decides to open and how fast it loses the bound glutamate may, in fact, be a mechanism to tell the cell about the rate at which signals are coming in," said Popescu. "The NMDA receptor may therefore be a device that translates the stimulation frequency into current amplitude: a bona-fide frequency discriminator."

Stimulus frequency carries information of particular interest to synaptic plasticity, widely believed to be the cellular basis of memory, said Popescu. "Often, stimuli that arrive at high frequency (100 or more per second) will cause a synapse to become more efficient or potentiated. Conversely, stimuli that arrive at a slower pace (about 10 per second) will cause the same synapse to become less responsive to subsequent stimulation or depressed. Scientists study the phenomena of long-term potentiation (LTP) and long-term depression (LTD) with great hope of understanding how we learn and how we form and recall memories. These processes are impaired in many neurological diseases.

"This work vividly demonstrates the value of learning about mechanism," she added. "Once we understand how things work, we often discover novel, unsuspected phenomena, which open new avenues for inquiry that, in turn, could lead to fresh strategies to treat or prevent malfunctions with devastating consequences."

The work was supported by grants from the National Institutes of Health to Popescu and Auerbach.

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