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Arc Protein Helps Translate Learning Into Memory

By delving into the inner workings of synapses, the junctions between brain cells, scientists have mapped how a protein called Arc helps regulate their activity to translate learning into long-term memory.

Steve Finkbeiner, a professor of neurology and physiology at the University of California San Francisco (UCSF), and colleagues, believe their discovery also offers a deeper understanding of what goes on at the molecular level when this activity is disrupted, with implications for Alzheimer's and other neurological disorders.

They write about their findings in a paper published online in Nature Neuroscience at the weekend.

Finkbeiner, who led the research at Gladstone Institutes, a neurological disease research center affiliated to UCSF, says in a statement:

"Scientists knew that Arc was involved in long-term memory, because mice lacking the Arc protein could learn new tasks, but failed to remember them the next day." Synapses Synapses are highly specialized junctions that process and relay signals between neurons or brain cells.

Although the synapses formed during our early brain development form the majority of those we shall ever have, they can be formed, broken and strengthened throughout the rest of our lives. The more active a synapse is, the stronger it gets: this is essential to making new memories.

But if synapses become over-active, they can over-stimulate neurons, which results in epileptic seizures, so somehow, the brain keeps synapse activity in check to stop this happening. Homeostatic Scaling Stops Synapses Getting Hyperactive One way the brain stops synapses getting too excited is a recently discovered process called "homeostatic scaling". The neuroscientists who discovered this process found it strikes a balance between synapse-strengthening and keeping synapse excitation in check.

But exactly how neurons strike this balance was somewhat of a mystery: although researchers suspected it had something to with the Arc protein.

"Because initial observations showed Arc accumulating at the synapses during learning, researchers thought that Arc's presence at these synapses was driving the formation of long-lasting memories," says Finkbeiner, although he and his team had other ideas. Lab Studies Reveal Three Regions Control Arc's Behavior So they set out to study the behavior of Arc in the lab: first in animals and then in culture.

They were surprised to discover that while Arc accumulates at the synapses when individual neurons are stimulated during learning, soon afterwards, most of the protein gets shuttled into the nucleus.

Lead author Erica Korb, says when they looked more closely, they saw how three regions in the protein were controlling its activity. One region exports the protein from the nucleus, another transports it into the nucleus, and the third keeps it there.

"The presence of this complex and tightly regulated system is strong evidence that this process is biologically important," she adds. Arc As Master Regulator of Homeostatic Scaling The team believes their experiments show Arc is a master regulator of homeostatic scaling.

Genes have to be switched on and off at precise times to produce the proteins that neurons use to form memories.

The team found Arc controls this activity, which is required for homeostatic scaling, from inside the nucleus of the neuron.

The process strengthens the synapses, allowing formation of long-term memory, without letting them become too excited. Findings Could Be Important for a Number of Neurological Diseases Finkbeiner says their finding could be important for a number of neurological diseases. Not just because it clarifies the role of Arc in the formation of long-term memory, but also because it offers "new insight into the homeostatic scaling process itself - disruptions in which have already been implicated in a whole host of neurological diseases".

For example in Alzheimer's disease, scientists have discovered that the hippocampus, the brain's memory center, has much lower levels of Arc than normal.

"It's possible that disruptions to the homeostatic scaling process may contribute to the learning and memory deficits seen in Alzheimer's," suggests Finkbeiner.

Disruption to Arc production and transport could also be a factor in autism. A common cause of autism and mental retardation is the genetic disorder Fragile X, which has a direct impact on how neurons produce Arc.

Korb says they hope further investigations of Arc and its effect on health and disease will offer even deeper understanding of these and other neurological disorders, plus lay the groundwork for new treatments.

Funds from the National Institute of Neurological Disease and Stroke, the National Institute on Aging and the Keck Foundation, plus a Ruth L. Kirschstein Fellowship, helped finance the study.

In another recently published study, researchers at the University of California Los Angeles suggest that healthy habits are linked to reduced memory loss.

While in another intriguing piece of research, scientists discovered that clenching your right hand may help create a stronger memory of an event or action, and clenching your left hand may help you recall the memory later.

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