Insulin receptor signaling in long-term memory consolidation following spatial learning

  1. Jing-Tao Dou1,4,
  2. Min Chen3,
  3. Franck Dufour1,
  4. Daniel L. Alkon1, and
  5. Wei-Qin Zhao1,2,5
  1. 1Blanchette Rockefeller Neurosciences Institute, Rockville, Maryland 20850 USA2 Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, USA3 Metabolic Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA4 Department of Endocrinology, PLA General Hospital, Beijing 100853 China

Abstract

Evidence has shown that the insulin and insulin receptor (IR) play a role in cognitive function. However, the detailed mechanisms underlying insulin's action on learning and memory are not yet understood. Here we investigated changes in long-term memory-associated expression of the IR and downstream molecules in the rat hippocampus. After long-term memory consolidation following a water maze learning experience, gene expression of IR showed an up-regulation in the CA1, but a down-regulation in the CA3 region. These were correlated with a significant reduction in hippocampal IR protein levels. Learning-specific increases in levels of downstream molecules such as IRS-1 and Akt were detected in the synaptic membrane accompanied by decreases in Akt phosphorylation. Translocation of Shc protein to the synaptic membrane and activation of Erk1/2 were also observed after long-term memory formation. Despite the clear memory-correlated alterations in IR signaling pathways, insulin deficits in experimental diabetes mellitus (DM) rats induced by intraperitoneal injections of streptozotocin resulted in only minor memory impairments. This may be due to higher glucose levels in the DM brain, and to compensatory mechanisms from other signaling pathways such as the insulin-like growth factor-1 receptor (IGF-1R) system. Our results suggest that insulin/IR signaling plays a modulatory role in learning and memory processing, which may be compensated for by alternative pathways in the brain when an insulin deficit occurs.

Footnotes

  • Article published online ahead of print. Article and publication date are at http://www.learnmem.org/cgi/doi/10.1101/lm.88005.

    • Accepted August 29, 2005.
    • Received October 15, 2004.
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