Calcium-Stimulated Adenylyl Cyclases are Critical Modulators of Fear Learning and Experience-Dependent Plasticity

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 Ca<super>2+</super>-stimulated adenylyl cyclases: AC), AC1 and AC8, in modulating fear memory. Ca<super>2+</super>-stimulated AC activity couples neuronal activity and intracellular Ca<super>2+</super> 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 Ca<super>2+</super>-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 Ca<super>2+</super>-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 Ca<super>2+</super>-stimulated AC activity modulates plasticity at the behavioral level as well. From these studies, I have observed a critical role for Ca<super>2+</super>-stimulated AC activity in modulating the consolidation and retention of fear memory and experience-dependent plasticity.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biology and Biomedical Sciences: Neurosciences

Year dc:date.available

2012

Author dc:creator

• Wieczorek, Lindsay

Contributors dc:contributor

• Louis Muglia

• Neurosciences
• Endocrinology
• Behavioral sciences
• adenylate cyclase
• adenylyl cyclase
• environmental enrichment
• learning
• memory
• stress

Language dc:language

English (en)

DOI

https://doi.org/10.7936/K7Z899FN

OAI identifier oai:identifier

oai:openscholarship.wustl.edu:etd-1665