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Mouse Models, KOs, Transgenics, and Gene Expression Monoamine Systems

$360,530P50FY2007MHNIH

Duke University, Durham NC

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Abstract

Depression is a psychiatric disorder where disturbance of mood is a prominent feature. Although the[unreadable] etiology of depression is unknown, alterations in serotonergic and noradrenergic function are[unreadable] implicated in the condition. The present Conte Center Grant proposes to examine depression from[unreadable] perspectives of functional imaging, morphometrics, and pharmacological interventions in humans, as[unreadable] well as though mouse genetic, molecular, biochemical, behavioral, and electrophysiological models[unreadable] of depression. The overall objective of the present proposal is to show how the norepinephrine (NE)[unreadable] and serotonin (5-HT) systems are interdependent in the development and amelioration of symptoms[unreadable] of depression, and to reveal novel mechanisms that contribute to the disorder. There are three major[unreadable] Aims. AIM 1: The roles in depression of the NE transporter, 5-HT transporter, and vesicular[unreadable] monoamine transporter 2 will be investigated. Effects of antidepressants on monoamine and[unreadable] metabolite levels in various brain regions will be studied. Molecular fingerprinting of signal[unreadable] transduction pathways will be used to analyze effects of genotype and antidepressant treatment. AIM[unreadable] 2: The role in depression of glycogen synthase kinase-3beta (GSK3b) will be analyzed. Mice will be[unreadable] developed that have GSK3b selectively deleted in the CNS. Animals will be evaluated according to[unreadable] behavioral, neurotransmitter, and signal transduction responses to antidepressants. AIM 3: Mice will[unreadable] be made that bear the same polymorphisms in tryptophan hydroxylase 2 (Tph2) found in human[unreadable] depressed patients. Mutants will be examined according to behavioral, neurotransmitter, and signal[unreadable] transduction responses to antidepressants and electroconvulsive therapy.

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