X-Message-Number: 23413
From: "Basie" <>
Subject: Long term memory mystery unraveled
Date: Mon, 9 Feb 2004 22:49:10 -0500

MIT Team Discovers Memory Mechanism
CAMBRIDGE, Mass. -- MIT neuroscientists have discovered a new brain
mechanism controlling the formation of lasting memories. This mechanism
explains how signals between neurons stimulate production of the protein
building blocks needed for long-term memory storage.

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Related section: Mind & Brain



The study, which will appear in the Feb. 6 issue of the journal Cell, has
broad implications for our understanding of how learning and memory normally
occur, and how these abilities may be undermined in psychiatric and
neurologic diseases.

Long-lasting memories are stored in the brain through strengthening of the
connections, or synapses, between neurons. Researchers have known for many
years that neurons must turn on the synthesis of new proteins for long-term
memory storage and synaptic strengthening to occur, but the mechanisms by
which neurons accomplish these tasks have remained elusive.

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
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."

An immediate question that Tonegawa and colleagues are pursuing is how
neurons target the newly synthesized proteins to the specific synapses
participating in memory formation while not modifying other synapses.

In addition to Tonegawa and Kelleher, the study's other authors (all in
Tonegawa's lab) are graduate student Arvind Govindarajan and postdoctoral
fellows Hae-Yoon Jung and Hyejin Kang.

Potential clinical impact

About the potential clinical impact of the study, Tonegawa observed, "As we
continue to map out the molecular and cellular mechanisms of cognitive
function, we will better understand the basis of disorders of memory
impairment. Improved understanding makes it far more likely that we can
develop drugs for specific molecular targets."

Defects in the strengthening and growth of synaptic connections are
associated with a variety of psychiatric and neurologic conditions affecting
the developing and adult brain, raising the possibility that disturbances in
the mechanism identified in this study may contribute to these disorders,
said Tonegawa. The next step will be to determine whether abnormalities in
the regulation of protein synthesis can be identified in the affected brain
regions in specific neuropsychiatric disorders.

###

The study was supported by the National Institutes of Health, the Howard
Hughes Medical Institute and the RIKEN Brain Science Institute.

Editor's Note: The original news release can be found here.

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