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J. Biol. Chem., Vol. 282, Issue 37, 27527-27535, September 14, 2007

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ERK and mTOR Signaling Couple -Adrenergic Receptors to Translation Initiation Machinery to Gate Induction of Protein Synthesis-dependent Long-term Potentiation^*

Jennifer N. Gelinas¹², Jessica L. Banko¹, Lingfei Hou^¶, Nahum Sonenberg^||, Edwin J. Weeber^**, Eric Klann^¶3, and Peter V. Nguyen⁴

From the Departments of Physiology and Psychiatry, and Centre for Neuroscience, University of Alberta School of Medicine, Edmonton, Alberta T6G 2H7, Canada, the Departments of Molecular Physiology and Biophysics and ^**Pharmacology, Vanderbilt Medical Center, Nashville, Tennessee 37232, the ^¶Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, and the ^||Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada

-Adrenergic receptors critically modulate long-lasting synaptic plasticity and long-term memory in the mammalian hippocampus. Persistent long-term potentiation of synaptic strength requires protein synthesis and has been correlated with some forms of hippocampal long-term memory. However, the intracellular processes that initiate protein synthesis downstream of the -adrenergic receptor are unidentified. Here we report that activation of -adrenergic receptors recruits ERK and mammalian target of rapamycin signaling to facilitate long-term potentiation maintenance at the level of translation initiation. Treatment of mouse hippocampal slices with a -adrenergic receptor agonist results in activation of eukaryotic initiation factor 4E and the eukaryotic initiation factor 4E kinase Mnk1, along with inhibition of the translation repressor 4E-BP. This coordinated activation of translation machinery requires concomitant ERK and mammalian target of rapamycin signaling. Taken together, our data identify distinct signaling pathways that converge to regulate -adrenergic receptor-dependent protein synthesis during long-term synaptic potentiation in the hippocampus. We suggest that -adrenergic receptors play a crucial role in gating the induction of long-lasting synaptic plasticity at the level of translation initiation, a mechanism that may underlie the ability of these receptors to influence the formation of long-lasting memories.

Received for publication, February 5, 2007 , and in revised form, June 15, 2007.

^* This work was supported by grants from the Canadian Institutes of Health Research and Alberta Heritage Foundation for Medical Research (to P. N.), a Canadian Institutes of Health Research team grant (to N. S.), National Institutes of Health Grants AG022574 (to E. W.), NS0304007, and NS047384, and FRAXA Research Foundation grant (to E. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Supported by M.D.-Ph.D. Studentships from Alberta Heritage Foundation for Medical Research and Canadian Institutes of Health Research.

³ Present address: Center for Neural Science, New York University, New York, NY 10003.

⁴ Faculty Senior Scholar of the Alberta Heritage Foundation for Medical Research. To whom correspondence should be addressed: University of Alberta, Dept. of Physiology, Medical Sciences Building, Edmonton, AB, T6G 2H7, Canada. Tel.: 1-780-492-8163; Fax: 1-780-492-8915; E-mail: peter.nguyen{at}ualberta.ca.

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