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The Journal of Neuroscience, August 2, 2006, 26(31):8048-8056; doi:10.1523/JNEUROSCI.0671-06.2006

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Behavioral/Systems/Cognitive
Spatial Memory Formation and Memory-Enhancing Effect of Glucose Involves Activation of the Tuberous Sclerosis Complex–Mammalian Target of Rapamycin Pathway

Pramod K. Dash, Sara A. Orsi, and Anthony N. Moore

The Vivian L. Smith Center for Neurologic Research and Department of Neurobiology and Anatomy, The University of Texas Medical School, Houston, Texas 77225

Correspondence should be addressed to Pramod K. Dash, Department of Neurobiology and Anatomy, The University of Texas Medical School, P.O. Box 20708, Houston, TX 77225. Email: p.dash{at}uth.tmc.edu

The tuberous sclerosis complex–mammalian target of rapamycin (TSC–mTOR) cascade integrates growth factor and nutritional signals to regulate the synthesis of specific proteins. Because both growth factor signaling and glucose have been implicated in memory formation, we questioned whether mTOR activity is required for long-term spatial memory formation and whether this cascade is involved in the memory-augmenting effect of centrally applied glucose. To test our hypothesis, we directly administered rapamycin (an inhibitor of mTOR), glucose, 5-aminoimidazole-4-carboxamide-1-4-ribonucleoside (AICAR; an activator of AMP kinase), or glucose plus rapamycin into the dorsal hippocampus after we trained rats in the Morris water maze task. The results from these studies indicate that glucose enhances, whereas AICAR and rapamycin both impair, long-term spatial memory. Furthermore, the memory-impairing effect of targeted rapamycin administration could not be overcome by coadministration of glucose. Consistent with these behavioral results, biochemical analysis revealed that glucose and AICAR had opposing influences on the activation of the TSC–mTOR cascade, as indicated by the phosphorylation of ribosomal S6 kinase (S6K) and 4E binding protein 1 (4EBP1), targets of mTOR. Together, these findings suggest that memory formation requires the mTOR cascade and that the memory-enhancing effect of glucose involves its ability to activate this pathway.

Key words: AICAR; glucose; hippocampus; rapamycin; spatial memory; tuberous sclerosis complex

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Received Feb. 15, 2006; revised June 2, 2006; accepted June 23, 2006.

Correspondence should be addressed to Pramod K. Dash, Department of Neurobiology and Anatomy, The University of Texas Medical School, P.O. Box 20708, Houston, TX 77225. Email: p.dash{at}uth.tmc.edu

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