Discovery could lead to treatments for learning and memory deficits, particularly Noonan鈥檚 syndrome
Cold Spring Harbor, NY — 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 黑料吃瓜资源 (CSHL) have now discovered how this so-called 鈥渟pacing effect鈥� is controlled in the brain at the level of individual molecules.
鈥淎lthough 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,鈥� says Zhong. 鈥淲e have shown for the first time that the spacing effect has a genetic and molecular basis.鈥�
Not only that, but Zhong鈥檚 team has also found that the duration of the resting intervals can be manipulated for achieving better memory by genetically altering SHP-2 phosphatase. 鈥淭his ability to exploit the spacing effect鈥檚 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,鈥� 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鈥檚 syndrome, a genetically inherited disease with an incidence rate of 1 in 1000 to 1 in 2000 people. More than 50% of Noonan鈥檚 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鈥檚 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鈥檚 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. 鈥淭he repeated formation and decay of the biochemical signal during each rest interval induces long-term memory,鈥� 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. 鈥淎 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,鈥� explains Zhong. 鈥淪o it鈥檚 crucial that the period of rest should last as long as it takes for a signal wave to form and reset.鈥�
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. 鈥淭hese findings suggest that SHP-2 phosphatase acts as a molecular timer that determines how long resting intervals should last,鈥� says Zhong.
Reversing memory deficits
Zhong鈥檚 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.
鈥淥ur results suggest that longer resting intervals for Noonan鈥檚 patients might reverse their memory deficits,鈥� 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鈥檚.
Written by: Peter Tarr, Senior Science Writer | [email protected] | 516-367-8455
Citation
鈥淪pacing Effect: SHP-2 Phosphatase Regulates Resting Intervals Between Learning Trials in Long-Term Memory Induction鈥� appears in the October 2nd issue of Cell. The full citation is: Mario R. Pagani, Kimihiko Oishi, Bruce D. Gelb and Yi Zhong. The paper is available online at (doi:10.1016/j.cell.2009.08.033).