Date of Award

1-1-2011

Document Type

Campus Access Dissertation

Department

Biomedical Science

First Advisor

Lawrence Reagan

Abstract

Several studies have shown that insulin induces synaptic plasticity in the hippocampal formation. In particular, it has been shown that insulin produces long term depression (LTD) in region CA1 of the juvenile and mature rat hippocampus. Using western blot analysis and field potential slice electrophysiology, I performed studies to further investigate the mechanisms underlying insulin-LTD. In addition, I examined the age-dependent differences in these processes and studied the role of insulin receptor signaling in insulin-LTD. My data revealed that insulin caused LTD in region CA1 of juvenile, but not mature rats. Furthermore, I observed age-dependent differences in insulin stimulated phosphorylation of Akt (pAkt) and p44/42MAP kinase (Pp44/42). More specifically, in juvenile and mature animals insulin caused an increase in pAkt; however, the effect of insulin on pAkt was longer lasting in mature animals. In juvenile animals, insulin caused a significant decrease in Pp44. In mature animals, insulin caused a significant decrease in Pp42. As I continued my investigation into the mechanisms underlying insulin-induced synaptic plasticity I observed that insulin age-dependently caused a decrease in the surface expression of the GluA2 and GluA1 subunits; and that insulin caused a decrease in phosphorylation of the GluA1 subunit on the S845 residue. In both juvenile and mature animals, inhibition of N-methyl-D-aspartate receptors (NMDARs) or phosphatidylinositol 3-kinase (PI3K) did not block insulin-LTD. Interestingly, in mature animals, insulin applied in the presence of a PI3K inhibitor converted transient depression into lasting depression that looked similar to insulin-LTD observed in juvenile hippocampal preparations. Collectively, these data show that insulin has complex interactions in the region CA1 of the hippocampus, especially with (á-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor) AMPAR subunits. Furthermore, these data suggest that insulin signaling molecules affect insulin-induced synaptic plasticity in an age-dependent manner. These data provide a potential mechanism by which insulin modulates memory. If indeed insulin modulation of memory occurs via insulin's ability to induce synaptic plasticity, these data suggest that insulin may modulate hippocampal-dependent memory differently depending upon an animal's age.

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