These findings, reported today in Nature Neuroscience, also offer newfound understanding as to what goes on at the molecular level when this process becomes disrupted.
Led by Gladstone Senior Investigator Steve Finkbeiner, MD, PhD, this research delved deep into the inner workings of synapses. Synapses are the highly specialized junctions that process and transmit information between neurons. Most of the synapses our brain will ever have are formed during early brain development, but throughout our lifetimes these synapses can be made, broken and strengthened.
Synapses that are more active become stronger, a process that is essential for forming new memories. However, this process is also dangerous, as it can overstimulate the neurons and lead to epileptic seizures. It must therefore be kept in check.
Neuroscientists recently discovered one important mechanism that the brain uses to maintain this important balance: a process called "homeostatic scaling." Homeostatic scaling allows individual neurons to strengthen the new synaptic connections they've made to form memories, while at the same time protecting the neurons from becoming overly excited. Exactly how the neurons pull this off has eluded researchers, but they suspected that the Arc protein played a key role.
"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," said Dr. Finkbeiner, who is also a professor of neurology and physiology at the University of California, San Francisco (UCSF), with which Gladstone is affiliated. "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."
But Dr. Finkbeiner and his team thought there was something else in play. In laboratory experiments, first in animal models and then in greater detail in the petri dish, the researchers tracked Arc's movements. And what they found was surprising.
"When individual neurons are stimulated during learning, Arc begins to accumulate at the synapses—but what we discovered was that soon after, the majority of Arc gets shuttled into the nucleus," said Erica Korb, PhD, the paper's lead author who completed her graduate work at Gladstone and UCSF. "A closer look revealed three regions within the Arc protein itself that direct its movements: one exports Arc from the nucleus, a second transports it into the nucleus, and a third keeps it there. The presence of this complex and tightly regulated system is strong evidence that this process is biologically important."
In fact, the team's experiments revealed that Arc acted as a master regulator of the entire homeostatic scaling process. During memory formation, certain genes must be switched on and off at very specific times in order to generate proteins that help neurons lay down new memories. From inside the nucleus, the authors found that it was Arc that directed this process required for homeostatic scaling to occur. This strengthened the synaptic connections without overstimulating them—thus translating learning into long-term memories.
"This discovery is important not only because it solves a long-standing mystery on the role of Arc in long-term memory formation, but also gives new insight into the homeostatic scaling process itself—disruptions in which have already been implicated in a whole host of neurological diseases," said Dr. Finkbeiner. "For example, scientists recently discovered that Arc is depleted in the hippocampus, the brain's memory center, in Alzheimer's disease patients. It's possible that disruptions to the homeostatic scaling process may contribute to the learning and memory deficits seen in Alzheimer's."
Dysfunctions in Arc production and transport may also be a vital player in autism. For example, the genetic disorder Fragile X syndrome—a common cause of both mental retardation and autism, directly affects the production of Arc in neurons.
"In the future," added Dr. Korb, "we hope further research into Arc's role in human health and disease can provide even deeper insight into these and other disorders, and also lay the groundwork for new therapeutic strategies to fight them."
Support for this research was provided by a Ruth L. Kirschstein Fellowship, the National Institute of Neurological Disease and Stroke, the National Institute on Aging and the Keck Foundation.
About the Gladstone Institutes
Gladstone is an independent and nonprofit biomedical-research organization dedicated to accelerating the pace of scientific discovery and innovation to prevent, treat and cure cardiovascular, viral and neurological diseases. Gladstone is affiliated with the University of California, San Francisco.
Anne Holden | EurekAlert!
Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY
NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation
A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.
The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
20.07.2018 | Power and Electrical Engineering
20.07.2018 | Information Technology
20.07.2018 | Materials Sciences