Semester

Fall

Date of Graduation

2011

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

James M O Donnell

Abstract

The effects of treatment with PDE4 inhibitors on cAMP/pCREB signaling, hippocampal neurogenesis and immobility in forced-swim test and the effects of DISC1 mutation on cAMP/pCREB signaling, PDE4 subtypes and PDE4 activity and high-affinity rolipram binding state were determined. Acute treatment with PDE4 inhibitors increased cAMP and pCREB transiently, as determined by ELISA and Western blotting, respectively. Repeated treatment with PDE4 inhibitors for 16 days produced antidepressant-like effect as evidence by decreased immobility in forced-swim test, increased cAMP/pCREB signaling and enhanced hippocampal neurogenesis. PDE4 inhibitors which preferentially interact with the high-affinity rolipram binding state, such as rolipram and piclamilast, produced greater effects than CDP840, which preferentially interacts with the low-affinity rolipram binding state.;PDE4 exerts its normal functions by interacting with a variety of binding proteins. The effects of mutation of one of the most important binding proteins DISC1, a risk factor gene for mental disorders, were determined. In this study, DISC1 mutant mice that carried truncated DISC1 proteins were used. DISC1 mutation increased cAMP and pCREB levels, and decreased PDE4 activity in prefrontal cortex, hippocampus and striatum. The PDE4B1, B3 and B4 splice variants were decreased in these three brain regions, while the D3 and D5 variants were decreased only in the hippocampus; PDE4A1 and A5 splice variants were not affected by the DISC1 mutation. Previous work has shown greater DISC1 association with the PDE4B subtype than the other subtypes. Radioligand binding assays showed that the high affinity rolipram binding state was decreased in brain regions of DISC1 mutant mice, suggesting high affinity rolipram binding state is functionally associated with DISC1.;Overall, PDE4 inhibitors which preferentially interact with the high-affinity rolipram binding states produced greater effects on cAMP/pCREB and behavior, as well as for increasing hippocampal neurogenesis. In addition, DISC1 mutation decreased PDE4 activity and upregulated cAMP/pCREB levels. These suggest DISC1 is important for the normal function of PDE4 and downstream cAMP signaling. Mutation of DISC1 also induced a decrease in PDE4B and PDE4D, but not PDE4A splice variants. The studies shed light on the understanding of the function of high-affinity rolipram binding state in the central nervous system and may provide a new target for antidepressant drug discovery and development.

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