Semester

Summer

Date of Graduation

2014

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Han-Ting Zhang

Committee Co-Chair

Stanley Hileman

Committee Member

Rae Matsumoto

Committee Member

James O'Donnell

Committee Member

Adrienne Salm

Committee Member

Bernard Schreurs

Abstract

Cognitive disorders such as depression, anxiety, and senescent-induced memory loss are a growing pandemic in the world. Anxiety is the most common psychiatric disorder in America, affecting upwards of 50 million people a year; depression has a lifetime prevalence of 20% of the population, and it's predicted pathological memory disorders such as Alzheimer's disease (AD) will reach exponential levels by the year 2050. While there are treatments for anxiety and depression, far less success has been reached with therapeutics for AD. Phosphodiesterases (PDEs) may be a potential novel target for future therapeutics aimed at combatting these psychiatric illnesses and neurodegenerative diseases. PDEs are a "super family" of 11 smaller enzyme families expressed throughout the body that degrade the cyclic nucleotides cAMP and/or cGMP, essentially acting as an off switch for intracellular cAMP and/or cGMP signaling. In particular, one member of this family termed PDE4 is highly expressed in regions of the brain that may play a role in these psychiatric disorders such as the prefrontal cortex (PFC), hippocampus, amygdala, and striatum. PDE4 has four subtypes (A, B, C, and D), of which only PDE4C is not highly expressed in the brain. It has been found through the use of genetic manipulation that PDE4D is highly involved with memory and depressive-like behavior, and PDE4B is involved with anxiety and release of inflammatory factors from immune cells; however, the functional role that PDE4A plays in behavior was not known. The purpose of this dissertation was to characterize the functional role of PDE4A in behavior through the use of PDE4A KO mice, and a battery of behavioral and biochemical tests. We found that PDE4A KO mice displayed a strong anxiogenic profile, and a prolonged release of corticosterone in response to a stressor. In addition, they also displayed enhanced emotional memory. PDE4A KO had no effect on depressive-like behavior, and decreased the training latency in the Morris Water Maze. PDE4A KO mice were also obese which was not due to hyperphagia or decreased locomotor activity. It was found that PDE4A KO decreased the levels of the major metabolic hormone T3. These results suggest that with further characterization, PDE4A may be a novel target in the future for anxiety or emotional memory disorders, as well as obesity.

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