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

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.Insulin/insulin receptor plays diverse roles in brain functions including learning and memory. Cognition-enhancing effects of insulin have been reported in both human and animal experiments (Kern et al. 1999(Kern et al. , 2001Park et al. 2000), whereas impairments in insulin and the brain insulin receptor (IR) have been linked to development of aging-associated brain degenerative disorders such as Alzheimer's disease (Craft et al. 1996;Frolich et al. 1998;Gasparini and Xu 2003;Watson and Craft 2003). Unlike its peripheral counterpart, insulin/insulin receptor in the brain does not appear to exert a direct effect on neuronal glucose metabolism, but most likely plays a modulatory role, via activating specific signal transduction cascades, in synaptic activities involved in memory formation. Evidence has shown that insulin/ insulin receptor is involved in regulation of neurotransmitter release (Bhattacharya and Saraswati 1991;Figlewicz and Szot 1991), receptor conductance and trafficking (Wan et al. 1997;Beattie et al. 2000;Lin et al. 2000;Man et al. 2000;Skeberdis et al. 2001;Zhou et al. 2001), and intracellular Ca 2+ release and neuropeptide secretion (Jonas et al. 1997). As a receptor tyrosine kinase, the insulin receptor in the hippocampus was shown to respond to learning experiences by alterations in its gene expression and activation of downstream molecules such as Shc/Erk1/2 in an early stage of memory formation (Zhao et al. 1999).Despite the accumulated evidence, contradictory results appear to exist regarding ...

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