Project Summary

Hanting Zhang, Ph.D. (Young Investigator 2006) of West Virginia University, will use animal models to study the role PDE4 enzymes play in adult hippocampal neurogenesis, a common action of antidepressant treatments. PDE4 consists of four subtypes (A, B, C, D). PDE4A and PDE4D are highly, and PDE4B is minimally, expressed in the hippocampus. Chronic treatment with rolipram, a selective PDE4 inhibitor, produces antidepressant-like effects and increases hippocampal neurogenesis, which is accompanied by increased CREB phosphorylation. cAMP/CREB signaling is essential for mediating neurogenesis. The PDE4 enzyme, which catalyzes cAMP breakdown, therefore may play an important role in this process. Chronic administration of the antidepressant fluoxetine increases neurogenesis and downregulates PDE4D. Mice deficient in PDE4D also exhibit antidepressive behavior. Dr. Zhang proposes that PDE4D is the primary PDE4 involved in cAMP/CREB signaling regulating neurogenesis. Using individual PDE4 subtype-deficient mice, neurogenesis, phosphorylation of CREB, and the effects of rolipram on these two measures in the hippocampus will be determined. Findings should help elucidate the mechanisms by which PDE4 regulates cAMP/CREB-mediated neurogenesis and antidepressant actions.

Program Area: MOOD DISORDERS\Unipolar

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