Date of Graduation

2015

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Neurology

Committee Chair

James M O'Donnell

Committee Co-Chair

Visvanathan Ramamurthy

Committee Member

Adrienne Salm

Committee Member

Usha Sambamoorthi

Committee Member

Hanting Zhang

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) are a super-family of enzymes that regulate intracellular levels of the second messengers, cyclic AMP and cyclic GMP. Multiple PDEs have been shown to play vital roles in the central nervous system, with involvement in mood, reward mechanisms, and learning and memory. PDE2 is of special interest due to its high level of expression in forebrain regions, which are specifically implicated in mood and memory processes. In the first set of experiments, the potential role of PDE2 in depression- and anxiety-like behaviors was investigated using the forced swim test, tail suspension test, elevated plus maze, hole-board and step-through passive avoidance tests, as well as the object recognition test (ORT). The PDE2-selective inhibitor, Bay 60-7550 (3 mg/kg) did not significantly alter any of the depression- or anxiety-like behaviors, but did significantly enhance memory in the ORT. In the next set of experiments, the ORT was used to investigate the effect of PDE2 inhibition on various stages of learning and memory. Bay 60-7550 was administered 30-120 min prior to training, 0, 1, or 3 hrs after training, or 30 min prior to recall testing. Next, inhibitors of the cAMP or cGMP signaling pathways were administered 30 min prior to the PDE2 inhibitors Bay 60-7550 or ND7001, to assess the role cyclic nucleotide signaling on PDE2 inhibitor-enhanced memory. Finally, changes in the phosphorylation of CREB at Ser-133 and VASP at Ser-239 were determined to confirm activation of cAMP and cGMP signaling by PDE2 inhibition at behaviorally relevant doses. Bay 60-7550 (3 mg/kg) significantly enhanced memory of mice in the ORT when given 30 min prior to training, immediately after training, or 30 min prior to recall. Inhibitors of the cGMP pathway blocked the memory-enhancing effects of both Bay 60-7550 (3 mg/kg) and ND7001 (3 mg/kg). Bay 60-7550 (3 mg/kg) significantly enhanced the phosphorylation of CREB and VASP, both targets of PKG. While PDE2 inhibition did not appear to play a major role in depression- and anxiety-like behaviors in these tests, future research will further elucidate the role of PDE2 in other mood-related behavior tests. Additionally, PDE2 does appear to play a major role in learning and memory, as seen in the ORT. Developing a greater understanding of the role of PDE-2 in these memory processes will allow for potential drug development for the intervention of a variety of human diseases related to cognitive decline and memory impairment, which plague millions of individuals each year.

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