Study Uncovers New Mechanism of Long-Term Memory Formation

By Eric Sauter and Mika Ono

Scientists at The Scripps Research Institute have identified specific features of neurons that are critical components of the learning process and the development of long-term memory.

The study showed that, after 24 hours of fear conditioning in mice, neurons in the brain's memory hub, the hippocampus, demonstrated an increased ability to retain newly synthesized proteins called AMPA receptors.

The findings were published in the February 22 edition (Volume 319, Number 5866) of the journal Science.

These results support the idea that AMPA receptors strengthen memories by becoming part of the synapses, the gaps between the ends of nerve fibers that are traversed by nerve impulses passing from one neuron to another. These impulses travel to and from spines, parts of the neuron that protrude in branch-like projections.

The scientists found increased molecular trafficking to only one particular type of spine, called the mushroom spine. The other types (the thin and the stubby spines) showed no changes.

"Our study found that, under fear conditioning, approximately 80 percent of mushroom spines attracted the newly synthesized AMPA receptors, compared to only 50 percent in non-conditioned animals," said Mark Mayford, an associate professor of cell biology and a member of the Institute for Childhood and Neglected Diseases at Scripps Research. "It suggests to us that the conditioned memory is occurring at these specific mushroom spines. And that AMPA receptors play a significant role in maintaining increased synaptic strength—a likely basis of long-term memory and learning."

This is first study that shows a distinct difference in molecular signaling among various spine types. While little is known about the function of differently shaped spines, the fact that their distribution is altered in various forms of retardation like Fragile X syndrome and Downs syndrome suggests they play significant roles in mental function.

New Light on Memory

The study sheds new light on how memory works at the molecular level. Although there is no definitive answer to how memory is formed, the most generally accepted theory is that changes occur in synapse strengths, and that this added strength forges memory. 

One key question in the development of long-term memory has been how new proteins—AMPA receptors—find the specific synapses involved in increased synaptic signaling strength.

To determine the role of AMPA receptors in this process, the Scripps Research scientists developed transgenic mice to monitor the trafficking and turnover of newly synthesized AMPA receptorss produced at the time of learning.

"Because AMPA receptors have shown the ability to change trafficking patterns and move into synapses during long-term potentiation, there was ample reason to think it was important to the learning process," Mayford said. "Consequently, we developed a mouse model that allowed us to monitor these new AMPA receptors visually with a green fluorescent stain as they traveled to the tagged synapses."

After fear conditioning had triggered new AMPA receptors deep in the neuron's nucleus, the researchers chemically suppressed any further expression of the proteins. This allowed time for the receptors to migrate to their appointed synapses. Hours later, green fluorescence revealed the fate of the specific AMPA receptors born in response to the learning.

The researchers found synapses that received the AMPA receptors with memory were limited to the mushroom type. The mushroom spines also figured prominently in the same neurons when the fear conditioning was reversed by repeatedly exposing the animals to the feared situation in a benign way, a procedure called extinction learning. This indicated that the same neurons are activated when a fear is learned and when it is lost. The surge in mushroom spine capture of the receptors appeared within hours of learning and was gone after a few days, but appeared to be critical for cementing the memory.

Thomas Insel, director of the National Institute of Mental Health (NIMH), part of the National Institutes of Health (NIH), which funded the study, noted, "Remarkably, this research demonstrates a way to untangle precisely which cells and connections harbor a particular memory. We are actually learning the molecular basis of learning and memory."

The study, Spine-Type Specific Recruitment of Newly Synthesized AMPA Receptors with Learning, was also supported by the NIMH and the Uehara Memorial Foundation. In addition to Mayford, authors of the study were Naoki Matsuo and Leon Reijmers of The Scripps Research Institute. See
http://www.sciencemag.org/cgi/content/abstract/319/5866/1104.

Send comments to: mikaono[at]scripps.edu

Newly synthesized AMPA glutamate receptors (green) were captured by mushroom-shaped spines in mouse hippocampus neurons encoding memory, after one (top), two (middle) and six (bottom) hours of stimulus. The receptors are thought to be key to strengthening the memory, making it long-term.