Brain insulin receptors and spatial memory - Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats

Evidence accumulated from clinical and basic research has indirectly implic ated the insulin receptor (IR) in brain cognitive functions, including lear ning and memory (Wickelgren, I. (1998) Science 280, 517-519), The present s tudy investigates correlative changes in IR expression, phosphorylation, an d associated signaling molecules in the rat hippocampus following water maz e training. Although the distribution of IR protein matched that of IR mRNA in most forebrain regions, a dissociation of the IR mRNA and protein expre ssion patterns was found in the cerebellar cortex. After training, IR mRNA in the CA1 and dentate gyrus of the hippocampus was up-regulated, and there was increased accumulation of LR protein in the hippocampal crude synaptic membrane fraction. In the CA1 pyramidal neurons, changes in the distributi on pattern of LR in particular cellular compartments, such as the nucleus a nd dendritic regions, was observed only in trained animals. Although IR sho wed a low level of in vivo tyrosine phosphorylation, an insulin-stimulated increase of in vitro Tyr phosphorylation of IR was detected in trained anim als, suggesting that learning may induce IR functional changes, such as enh anced receptor sensitivity. Furthermore, a training-induced co-immunoprecip itation of IR with Shc-66 was detected, along with changes in in vivo Tyr p hosphorylation of Shc and mitogen-activated protein kinase, as well as accu mulation of Shc-66, Shc-52, and Grb-2 in hippocampal synaptic membrane frac tions following training. These findings suggest that IR may participate in memory processing through activation of its receptor Tyr kinase activity, and they suggest possible engagement of Shc/Grb-2/Ras/mitogen-activated pro tein kinase cascades.