February 09, 2004
MIT Researchers Find Molecular Pathway For Memory Formation

A kinase enzyme (which transfers a phosphate onto a protein - which often turns a protein into a less or more active state) called Mitogen-Activated Protein Kinase (MAPK) has been found to play a crucial role in increasing the synthesis of a large assortment of different proteins needed for long-term memory formation.

The MIT research team, led by Nobel laureate Susumu Tonegawa, director of the Picower Center for Learning and Memory, has now identified a crucial molecular pathway that allows neurons to boost their production of new proteins rapidly during long-term memory formation and synaptic strengthening.

"What we have discovered that hasn't been established before is that there is a direct activational signal from the synapse to the protein synthesis machinery," said Tonegawa, the Picower Professor of Biology and Neuroscience in MIT's Departments of Brain and Cognitive Sciences and Biology The central component of this pathway, an enzyme called "mitogen-activated protein kinase" (MAPK), effectively provides a molecular switch that triggers long-term memory storage by mobilizing the protein synthesis machinery.

Acting on a hunch that MAPK might be an important part of such a "memory switch," Ray Kelleher, a postdoctoral fellow in Tonegawa's laboratory and lead author of the study, created mutant mice in which the function of MAPK was selectively inactivated in the adult brain. Intriguingly, he found that these mutant mice were deficient in long-term memory storage. In contrast to normal mice's ability to remember a behavioral task for weeks, the mutant mice could remember the task for only a few hours. Similarly, the researchers found that synaptic strengthening was also much more short-lived in neurons from the mutant mice than in neurons from normal mice.

Realizing that the pattern of impairments in mutant mice suggested a problem with the production of new proteins, the researchers then performed an elegant series of experiments that revealed precisely how MAPK translates synaptic stimulation into increased protein synthesis. Based on molecular comparisons of neurons from normal and mutant mice, they found that synaptic stimulation normally activates MAPK, and the activated form of MAPK in turn activates several key components of the protein synthesis machinery. This direct regulation of the protein synthesis machinery helps explain the observation that activation of MAPK enhanced the production of a broad range of neuronal proteins.

"Many people had thought that long-term memory formation involved only boosting the synthesis of a very limited set of proteins," said Tonegawa. "But to our surprise, this process involves 'up-regulating' the synthesis of a very large number of proteins."

This information may be useful for researchers trying to develop memory formation enhancement drugs. A drug that upregulates MAPK synthesis or that turns on its activity might have the effect of enhancing memory formation.

As the steps in memory formation becomes identified and better understood they all become potential targets for drug therapies. The same holds true for emotional reactions and other aspects of cognitive function. As any biological system becomes better understood it becomes more manipulable. Where is this all going to lead? It seems likely that most people 30 or 40 years from now will be using drugs to enhance and fine-tune the performance their brains in a variety of ways. While many people use drugs today for either recreation purposes or to treat mental disorders it seems likely that the focus of drug use for altering the mind will shift toward cognitive enhancement in the future both to improve thinking and to align one's emotional reactions more closely with goals one wants to achieve..

Share |      Randall Parker, 2004 February 09 11:58 PM  Brain Memory


Comments
jm said at February 10, 2004 8:53 AM:

Foreword: I haven't read the Cell paper and I have a great deal of respect for the work that was required to develop the mouse model...impressive.

That being said, I think anyone who has worked with MAPK much would kindof shrug their shoulders and say, "Yea, that is MAPK's role pretty much everywhere" (I know, I know...it has to be proven by experimentation so I don't mean to take anything away, esp. having spent years in cell signaling/biomedical research). Their next steps should be relating the temporal pattern of MAPK activation to either long-term memory or short-term memory (similar to what has been done with differentiation of pheochromocytoma cells years ago). Also, seems likely their findings are strongly related to cellular plasticity (requiring cell movement...strongly correlated with MAPK activation).

Regarding the thoughts on use of drugs to enhance memory/control emotions, imho MAPK is not a great target since it is such a non-specific player (it is activated by oxygen, growth factors, physical forces (osmotic etc), UV light, etc. etc. etc.) Investigators have searched for the "specificity" in cytosolic signal transduction pathways for years with great difficulty. Also, you certainly don't want to over-stimulate (associations published with oncogenesis). Not saying it is impossible, but to generalize about simply controlling MAPK makes it seem way too easy.

erk said at March 5, 2004 12:29 AM:

Actually, if jm had read the paper, he would have found that the investigators demonstrate a very clear requirement for MAPK in long-term memory and NOT short-term memory. These findings parallel nicely the role for MAPK that they demonstrate in the regulation of protein synthesis, since protein synthesis is required for the conversion of short-term to long-term memory. There are several other inaccuracies in jm's statement that warrant correction. First, there are multiple distinct MAPK cascades in mammalian cells. The MAPK subfamilies activated by "oxygen, physical forces (osmotic), UV light, etc." are distinct from those activated by "growth factors." Specifically, it is the p38 and JNK cascades that are activated by cellular stress, while the ERK cascade is activated by growth factors. Second, cellular plasticity means different things in different tissues, and plasticity in the adult central nervous system is NOT associated with cellular movement, as in the case of fibroblasts, but rather with the formation of new synaptic connections. Finally, the important implications of this study include the identification of multiple MAPK targets within the general translational machinery. Most neuroscientists would agree that enhancement of protein synthesis in conditions where synaptic plasticity and learning are impaired, such as aging and Alzheimer's disease, offers a very interesting and promising therapeutic approach.

KHAWAJA EHTESHAM said at October 2, 2005 11:44 AM:

HI
IM DOCTOR I M WORKING IN THIS FIELD FOR THE LAST 5 YEARS
BECOZ I THINK SO IF I CAN ABLE TO DEVELOP THIS THING I WILL ABLE TO STORE INFORMATION FOR A LONG TIME I HAVE DEVELOP CERTAIN WAYS TO ENHANCE IT BUTNOT SUCCEDED FULLY TILL NOW
CAN U HELP ME IN THIS REGARD IWILL BE VERY GRATE FULL OF U IM ALSO WANT TO DO SOME RESEARCH ON THIS TOPIC

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