Neuroscience News

ST. PAUL, Minn. – New guidelines from the American Academy of Neurology identify the most effective treatments for amyotrophic lateral sclerosis (ALS), often called Lou Gehrig’s disease. The guidelines are published in the October 13, 2009, issue of Neurology®, the medical journal of the American Academy of Neurology.

“While we are waiting for a cure, people need to know that a lot can be done to make life easier and longer for people with ALS,” said lead guidelines author Robert G. Miller, MD, with the Department of Neurology at California Pacific Medical Center in San Francisco and Fellow of the American Academy of Neurology.

ALS is a rapidly progressive and fatal neurologic disease that attacks the nerve cells that control voluntary muscles. Eventually people with ALS are not able to stand or walk, or use their hands and arms, and they have difficulty breathing and swallowing. Most people with ALS die within three to five years from the onset of symptoms. However, about 10 percent survive for 10 or more years.

According to the guidelines, the drug riluzole should be offered to people with ALS to slow the rate at which the disease progresses. Riluzole is the only drug approved by the U.S. Food and Drug Administration to treat ALS and has a modest effect on prolonging survival.

The guidelines also state that life expectancy will likely increase and quality of life may increase for people with ALS who use an assisted-breathing device. Longer life expectancy is also likely for people with ALS who use a feeding tube known as a PEG tube, since nutrition plays a critical role in prolonging survival. The guidelines also recommend doctors consider offering their patients botulinum toxin B to treat sialorrhea, also known as drooling, if oral medications do not help. Moreover, doctors should consider screening their patients for behavioral or thinking problems because studies show many people with ALS have these problems. Such problems might affect some patients’ willingness to accept suggested treatments.

“Important treatments available for people with ALS are often not suggested by doctors and not used by patients,” said Miller. “It’s important that people with ALS know that more treatments are now available to ease the burden of the disease and that they should see neurologists who are aware of these new guidelines and follow them.”

In addition, the guidelines recommend people with ALS enroll early in a specialized multidisciplinary ALS clinic to optimize care. “Attending a multidisciplinary clinic will likely increase survival and access to treatments, and may improve quality of life,” said Miller.

The cause of ALS is not known, and it’s not yet known why ALS strikes some people and not others.

About The American Academy of Neurology 

The American Academy of Neurology, an association of more than 21,000 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as epilepsy, dystonia, migraine, Huntington’s disease and dementia.

Discovery could lead to treatments for learning and memory deficits, particularly Noonan’s syndrome

Cold Spring Harbor, N.Y. – As most good students realize, repeated studying produces good memory. Those who study a lot realize, further, that what they learn tends to be preserved longer in memory if they space out learning sessions between rest intervals. Neuroscientists at Cold Spring Harbor Laboratory (CSHL) have now discovered how this so-called “spacing effect” is controlled in the brain at the level of individual molecules.

Led by Professor Yi Zhong, Ph.D., the CSHL team has found that a protein called SHP-2 phosphatase controls the spacing effect by determining how long resting intervals between learning sessions need to last so that long-lasting memories can form. The study, carried out in a fruit fly model, will appear online in the journal Cell on October 2.

“Although there are many theories that explain the spacing effect at the psychological level and hundreds of studies that back them up, there has not been any understanding of this phenomenon at the neurobiological level,” says Zhong. “We have shown for the first time that the spacing effect has a genetic and molecular basis.”

Not only that, but Zhong’s team has also found that the duration of the resting intervals can be manipulated for achieving better memory by genetically altering SHP-2 phosphatase. “This ability to exploit the spacing effect’s molecular control to enhance memory could be useful in a wide range of settings such as education, advertising, and most importantly, in treating learning and memory disorders,” says Zhong.

How excess protein activity impedes long-term memory

Zhong has long been interested in genes that when mutated trigger learning and memory disorders such as Noonan’s syndrome, a genetically inherited disease with an incidence rate of 1 in 1000 to 1 in 2000 people. More than 50% of Noonan’s patients have mutations in a gene called PTP11, which encodes the SHP-2 phosphatase protein. In contrast to many disease-related mutations that shut off protein production or impair protein activity, these PTP11 mutations do the opposite – they boost the activity levels of SHP-2 phosphatase.

To understand how this change impedes long-term memory, Zhong’s team engineered these mutations into a gene in fruit flies called corkscrew that is the functional equivalent of PTP11 in humans. The mutant flies were taught to avoid certain odors via a training regimen of repeated learning sessions broken up by resting intervals lasting 15 minutes. But this training regimen, which induces long-term memory in normal flies, failed to work in the mutants because the increased activity of SHP-2 phosphatase disturbed the spacing effect.

Zhong’s team found that normally, as each learning period ends, SHP-2 phosphatase activity inside stimulated neurons triggers a wave of biochemical signals, which have to peak and decay before the next learning session can begin. “The repeated formation and decay of the biochemical signal during each rest interval induces long-term memory,” explains Zhong.

In normal flies, these signal waves took 15 minutes to peak and decay. In the mutants that had excess protein activity, however, the signaling wave took 40 minutes to decay, the team discovered. “A training regimen that includes only 15 minute rest intervals therefore fails in the mutants because increased SHP-2 phosphatase activity somehow causes the waves of signals to fall out of sync,” explains Zhong. “So it’s crucial that the period of rest should last as long as it takes for a signal wave to form and reset.”

In contrast to increased SHP-2 phosphatase activity, which lengthened the resting interval to 40 minutes, the team found that increased production of the protein with normal activity could shorten the duration of the resting interval to 2.5 minutes. “These findings suggest that SHP-2 phosphatase acts as a molecular timer that determines how long resting intervals should last,” says Zhong.

Reversing memory deficits

Zhong’s team has succeeded in reversing memory deficits in mutant flies in two ways. Either reducing the activity of mutated SHP-2 phosphatase to normal levels with drugs or simply altering training regimens to include 40-minute rest intervals instead of the normal 15 minutes both established long-term memory in the mutants.

“Our results suggest that longer resting intervals for Noonan’s patients might reverse their memory deficits,” says Zhong. His team is currently collaborating with clinicians to determine whether this intervention, which worked in flies, will also work in people afflicted with Noonan’s.

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“Spacing Effect: SHP-2 Phosphatase Regulates Resting Intervals Between Learning Trials in Long-Term Memory Induction” appears in Cell on October 2nd. The full citation is: Mario R. Pagani, Kimihiko Oishi, Bruce D. Gelb and Yi Zhong.

Cold Spring Harbor Laboratory is a private, nonprofit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding of and ability to diagnose and treat cancers, neurological diseases and other causes of human suffering.

Contact:

Contact: Hema Bashyam
bashyam@cshl.edu
516-367-6822
Cold Spring Harbor Laboratory

New research in the FASEB Journal demonstrates role of IL-6 on sleep-related consolidation of specific types of memories, particularly during late night REM sleep cycles.

Good news for procrastinating students: a nasal spray developed by a team of German scientists promises to give late night cram sessions a major boost, if a good night’s sleep follows. In a research report featured as the cover story of the October 2009 print issue of The FASEB Journal, (http://www.fasebj.org) these scientists show that a molecule from the body’s immune system (interleukin-6) when administered through the nose helps the brain retain emotional and procedural memories during REM sleep.

“Sleep to remember, a dream or reality?” said Lisa Marshall, co-author of the study, from the Department of Neuroendocrinology at the University of Lubeck in Germany. “Here, we provide the first evidence that the immunoregulatory signal interleukin-6 plays a beneficial role in sleep-dependent formation of long-term memory in humans.”

To make this discovery, Marshall and colleagues had 17 healthy young men spend two nights in the laboratory. On each night after reading either an emotional or neutral short story, they sprayed a fluid into their nostrils which contained either interleukin-6 or a placebo fluid. The subsequent sleep and brain electric activity was monitored throughout the night. The next morning subjects wrote down as many words as they could remember from each of the two stories. Those who received the dose of IL-6 could remember more words.

“If a nasal spray can improve memory, perhaps we’re on our way to giving some folks a whiff of common sense, such as accepting the realities of evolution,” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “This is exciting piece of interdisciplinary science, since IL-6 had previously been considered a by-product of inflammation, not an agent that affects cognition.”

 Details: Christian Benedict, Jürgen Scheller, Stefan Rose-John, Jan Born, and Lisa Marshall. Enhancing influence of intranasal interleukin-6 on slow-wave activity and memory consolidation during sleep. FASEB J. 2009 23: 3629-3636. DOI: 10.1096/fj.08-122853