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Distributed September 23, 2004
Contact Wendy Lawton

Brain cells in the hippocampus make new long-term memories using a synapse-strengthening process called long-term potentiation, or LTP. In the current issue of Science, Brown University and Duke University Medical Center researchers shed new light on this critical brain function, describing where AMPA receptors are stored and how they are activated during LTP.

PROVIDENCE, R.I. — How information is stored in the nervous system, a key to memory and learning, is one of the hottest topics in neuroscience today. New research conducted at Brown University and Duke University Medical Center, published in the current issue of Science, fills in important details about cellular changes that occur when experience becomes memory.

This process is called long-term potentiation or LTP. When LTP occurs in the hippocampi, two curved regions that flank the center of the brain, changes occur in synapses. These connections between neurons – the major site for information exchange in the brain – become stronger after repeated stimulation. This increased synaptic strength can last hours, even days, and is believed to be the cellular basis for memory.

AMPA receptors on the membrane of the information-receiving neuron, known as the postsynaptic cell, act like gates, opening in response to chemical messages from a neighboring neuron. During LTP, extra AMPA receptors appear, increasing synaptic strength. But where do these extra receptors come from?

Michael Ehlers, associate professor of neurobiology at Duke, believed that recycling endosomes, or membrane-bound compartments inside neurons, carry a reserve pool of these receptors. To test his theory, Ehlers called on Julie Kauer at Brown.

Kauer, associate professor medical science in the Department of Molecular Pharmacology, Physiology and Biotechnology, proved that Ehlers’ theory was correct. By injecting mutant proteins marked with green fluorescent dye into the hippocampal neurons of rats, Kauer and her laboratory team found that AMPA receptors are indeed stored in recycling endosomes. When the neuron is stimulated, AMPA receptors leave this compartment and are rushed down the dendritic spine by three “chaperone” proteins – Rab11a, Rme1, and Syn13. These additional receptors are then inserted into the plasma membrane, boosting reception of memory-making information.

Based on those findings, the Brown and Duke team investigated another question: What if recycling endosomes carried more than AMPA receptors? In additional experiments with fluorescent dye and rat neurons, the team was surprised to learn during LTP, recycling endosomes also carry lipid molecules along with other “cargo” proteins that can be used to expand synapses during memory formation.

“It’s an exciting, essential finding,” said Kauer. “The more we understand the molecular and cellular mechanisms behind memory, the closer we are to treatments for disorders that affect memory.”

The hippocampus makes declarative memories – recollections of facts, events and word meanings. Scientists believe that certain forms of mental retardation and diseases such as Alzheimer’s are linked to nerve cell dysfunction in the hippocampus. The new research provides new targets for drugs or other treatments for these conditions.

Esther Penick and Jeffrey Edwards, postdoctoral research fellows in Kauer’s lab, worked on the study as did Mikyoung Park, a Duke graduate student. The National Institutes of Health, the American Heart Association, and the Alzheimer’s Association funded the research. Ehlers was also supported by a Broad Scholar Award.

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