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May 11, 2012

Japan Science and Technology Agency (JST)

The University of Tokyo

The law of the synapses: punishing the weak to maintain strong synapses strong

A novel molecular mechanism for long-lasting synaptic modulation that underlies learning and memory

Achievements Summary

Our brain possesses a huge capacity to store knowledge and to memorize distinct events of personal experiences throughout life span. Such mnemonic ability is believed to be accounted for, in part, by long-term synaptic plasticity, a cellular mechanism to tune up synaptic transmission efficacy between neurons and maintain this change over a long period of time. Lines of evidence have revealed that activity-dependent gene expression in the brain is crucial for long-term synaptic plasticity, but it has been unknown how protein products derived from such gene expression contribute to changing neuronal synaptic efficiency. An even larger mystery was to understand how newly expressed gene products selectively target the very synapses that needed to be modulated.

Associate Professor Haruhiko Bito and Dr. Hiroyuki Okuno at the Department of Neurochemistry, Graduate School of Medicine in the University of Tokyo, together with their colleagues and collaborators, tackled these questions and found a novel mechanism for regulating synaptic efficiency specifically in weak synapses. They focused on the activity-regulated gene product Arc and investigated Arc's dynamics in the synapses. Contrary to previous views, they found that Arc protein was targeted into inactive, weak synapses, rather than into active, strong synapses. Furthermore, this privileged accumulation of Arc in the weak synapses anti-correlated with the expression of glutamate receptors at these synapses. Because the amount of glutamate receptors directly determines synaptic efficacy between neurons in the brain, these results basically demonstrate that one critical role of Arc may be to keep weak synapses weak, while allowing strong, essential synapses to remain strong and capable of memory storage. The research group also showed that the selectivity of Arc targeting to the weak synapses was caused by a dynamic physical interaction of Arc with the β subunit of Ca2+/Calmodulin kinase II (CaMKIIβ), another key molecular player implicated in synaptic plasticity and memory formation.

This finding provides new mechanistic insights on how the contrast between strong and weak synapses may be maintained during long-term synaptic plasticity, and opens the door to a better understanding of the molecular basis of biochemical memory at individual synapses, and ultimately, of learning and memory.

Images

A dynamic CaMKIIβ-Arc interaction for glutamate receptor regulation. Rather than targeting strong synapses, up-regulated Arc targets weak synapses, and contributes to facilitating removal of glutamate receptors from the inactive postsynaptic membranes. The β isoform of CaMKII (CaMKIIβ) in the inactive synapse critically mediates such an “ inverse ” synaptic tagging process.

The original paper

Hiroyuki Okuno, Kaori Akashi, Yuichiro Ishii, Nan Yagishita-Kyo, Kanzo Suzuki, Mio Nonaka, Takashi Kawashima, Hajime Fujii, Sayaka Takemoto-Kimura, Manabu Abe, Rie Natsume, Shoaib Chowdhury, Kenji Sakimura, Paul F. Worley, and Haruhiko Bito. “ Inverse synaptic tagging of inactive synapses via dynamic interaction of Arc/Arg3.1 with CaMKIIβ ”

Cell, May 11, 2012, print issue.
doi: 10.1016/j.cell.2012.02.062

Links
Graduate School of Medicine
Department of Neurochemistry

Contact information

Haruhiko Bito, M.D., Ph.D.
Associate Professor
Department of Neurochemistry
The University of Tokyo,
Graduate School of Medicine
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Tel: +81(Japan)-3-5841-3559
Fax: +81(Japan)-3-3814-8154
E-mail:

Press contact:

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The University of Tokyo,
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