Neuronal signal transduction in hippocampus-dependent memory function.

摘要

This dissertation will describe two research projects examining the roles of intracellular signaling in neurons of the hippocampus with different aspects of memory processing. The first project identified a role for phosphatidylinositol 3 kinase (PI3K) signaling in the retrieval of memory. The second project examined the differential effects of calcium-stimulated adenylyl cyclase overexpression on memory in young adult and in aged mice. Both projects rely on rodent models of hippocampus-dependent memory behavior, and both seek to clarify specific contributions of signaling pathways to memory, which will be reviewed in Part I.;In Part II, the role of PI3K signaling in memory retrieval was examined. Retrieval is an aspect of memory that can be studied separately from other stages of memory processing. Here we report that memory retrieval of contextual fear stimulates the activity of PI3K in the hippocampus. Inhibition of PI3K activity in the hippocampus in vivo blocked contextual memory retrieval and extinction. Inhibitors of PI3K signaling also blocked increases in ERK/MAP kinase activity associated with memory retrieval. This suggests that PI3K activation in the hippocampus is critical for memory retrieval and is required for activation of ERK/MAP kinase in the hippocampus.;In Part III, we examined the effects of overexpression of Ca2+ -stimulated adenylyl cyclase on memory function of aged mice. Hippocampus-dependent memory requires a cAMP signal that is generated by Ca2+-stimulated adenylyl cyclases (AC1, AC8). Young transgenic mice overexpressing AC1 in the forebrain (AC1+ mice) have enhanced memory for novel object recognition. To determine if increasing AC1 expression improves memory in older mice, we analyzed fear, recognition, and spatial memory in mice aged to 25 months. Here we report that young adult AC1+ mice have enhanced social recognition memory. Surprisingly, aged AC1+ mice had poorer spatial memory than age-matched littermates. These data suggest that the decrease in Ca2+-stimulated adenylyl cyclase activity during aging of wild-type mice may be an adaptive mechanism required to maintain spatial memory function.