Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Neurosciences

Language

English (en)

Date of Award

1-1-2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Louis Muglia

Abstract

Stress can exacerbate psychiatric disease, often resulting in cognitive deficits. Consequently, a better understanding of what modulates stress-facilitated memory processing will help identify new targets for possible therapeutic intervention. Recent evidence suggests a role of the Ca2+-stimulated adenylyl cyclases: AC), AC1 and AC8, in modulating fear memory. Ca2+-stimulated AC activity couples neuronal activity and intracellular Ca2+ increases to the production of cAMP, and therefore, can very tightly regulate signal transduction after learning; yet, the details by which this occurs are not well understood. In this dissertation, I first investigated the temporal and regional importance of Ca2+-stimulated AC activity during different stages of memory processing using the tetracycline-off system, which allowed me to produce AC8 Rescue mice with forebrain-specific inducible expression of AC8 on an AC1 and AC8 double knockout: DKO) background. The results showed that forebrain Ca2+-stimulated AC activity was necessary to modulate long-term memory on several learning paradigms, and more specifically, that it was necessary during memory consolidation and retention. This finding is further supported by an overall decrease in transcriptional changes in DKO mice across several time points after conditioned fear: CF) learning, but most strikingly, at periods when memory consolidation and retention should be occurring. Since transcriptional changes are often dictated by synaptic activity and AC1 and AC8 are both localized at the synapse, I examined synaptic activity in DKO mice. Initial analysis of synaptic protein abundance in hippocampal cell cultures revealed decreased SV2 levels in DKO mice, but this can be rescued by infection with an AC8 lentivirus. Moreover, DKO mice also display synaptic deficits after learning as measured by p-synapsin. The CA1 LTP results coincide with the above data as DKO mice, but not AC8 Rescue mice, show impaired LTP. Finally, WT mice show changes in CF memory strength that is dependent on prior environmental exposure, but DKO mice do not, suggesting that Ca2+-stimulated AC activity modulates plasticity at the behavioral level as well. From these studies, I have observed a critical role for Ca2+-stimulated AC activity in modulating the consolidation and retention of fear memory and experience-dependent plasticity.

Comments

Permanent URL: http://dx.doi.org/10.7936/K7Z899FN

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