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Understanding Grows on Roots of Memory

A digital signal processing technique long used by statisticians to analyse data, is being applied to the brain in a novel endeavour by researchers from Rice University, Texas, to understand the roots of memory and learning, along with diseases such as Alzheimer's and Parkinson's and stroke.

The new technique, known as single molecule fluorescence resonance energy transfer or FRET has allowed views of single receptors in the nervous system as they go about their daily business.

The receptor is known as AMPA, and is a glutamate receptor which serves as signal control for fast transmission between cells in the central nervous system. If you will, its traffic control on the freeway.

Scientists have long thought these receptor proteins, which bind to glutamate to activate the flow of ions through the nervous system, are more than simple "on-off" switches. A "cleft" in the AMPA protein that looks and acts like a C-clamp and that binds the neurotransmitter glutamate may, in reality, serve functions at positions between fully open (off) and fully closed (on).

"In the old days, the binding was thought to be like a Venus flytrap," said Christy Landes, a Norman Hackerman-Welch Young Investigator Assistant Professor of Chemistry at Rice and lead author of the new paper. "The trap sat there waiting for something to come into the cleft. A neurotransmitter would come in and -- oops! -- it snapped shut on the molecule it was binding to, the gate opened up and ions would flow. We have all sorts of high-quality X-ray crystallography studies to show us what the snapped-open and snapped-shut cleft looks like."

The AMPA protein in open and closed positions

But X-ray images likely show the protein in its most stable -- not necessarily its most active -- conformation, she said. Spectroscopy also has its limits: If half the proteins in an assay are open and half are shut, the measured average is 50 percent, a useless representation of what's really going on.

The truth, Landes said, is that the clefts of AMPA receptors are constantly opening and closing, exploring their space for neurotransmitters. "We know these proteins are super dynamic whether glutamate is present or not," she said. "And we need to look at one protein at a time to avoid averaging."

Single-molecule FRET allowed Landes and her team to detect the photons emitted by the dyes. "These experiments had to be done in a box inside a box inside a box in a dark room," she said. "In a short period of measurement, we might be counting 10 photons."

Knowing how cleft positions match up with the function is valuable, said Jayaraman. This is an understatement of course, as any such increased understanding of the base signalling of the brain, opens up our understanding, and offers potential routes to control that process chemically, or to better understand how optogenetic interfaces with brain tissue will be routed.


Researchers get a grip on nervous system's receptors

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