Project Summary

Kwang-Soo Kim, Ph.D. (Independent Investigator 2003) of Harvard University, notes that in the brain, the neurotransmitter norepinephrine (NE) participates in diverse and essential functions of the nervous system including memory, mood, and cognition and its dysregulation is strongly implicated in major psychiatric illnesses such as mood disorders, schizophrenia, and attention deficit hyperactivity disorder (ADHD). NE neurotransmission is terminated by its rapid reuptake to presynaptic nerve terminals, mediated by the NE transporter (NET). Thus, NET is a key regulator of NE neurotransmission and is a prime target for antidepressant drugs as well as for illicit drugs such as cocaine and amphetamine. Despite its functional importance and clinical significance, molecular mechanisms underlying NET gene expression in the normal and diseased brain are poorly understood. In a previous NARSAD Independent Investigator Award, Dr. Kim successfully studied some aspects of NET gene regulation. He now proposes to characterize transgenic mice as a model of NET gene regulation in the developing and adult brain. He hopes to delineate critical promoter regions that govern in vivo NET gene expression in a specific spatio-temporal fashion and establish invaluable animal models for the further study of NET gene regulation. He will also seek to identify critical transcription factors and investigate their mechanistic role in NET gene expression. Finally, he will attempt to determine if identified novel human-NET (hNET) promoter mutations may be risk factors in psychiatric disorders such as mood disorders and ADHD. He will perform genetic association studies using DNA samples from patients with mood disorders and ADHD and compare them with those from ethnically matched control subjects available in his laboratory. This study will advance basic understanding of NET gene regulation during development at the molecular and systemic level and will directly address whether its functional promoter variations may associate with psychiatric disorders. Thus, the proposed experiments may shed new insights on the biological basis of NE-related psychiatric disorders.

Program Area: MOOD DISORDERS\Unipolar Depression

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