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Scientific Report 2007

Scripps Florida


Identification of Genetic Determinants of Depression

M.T. Pletcher, K.J. Clarke, B.C. Long, B.H. Miller, L.E. Schultz, B.M. Young

Clinical depression is a mood disorder with high morbidity and mortality that is estimated to occur in more than 15% of the adult population in the United States. Depression has a wide range of symptoms, including loss of energy, changes in weight, diminished interest or pleasure in daily activities, insomnia or excessive sleep, anxiety, slowness of movement, feelings of worthlessness, difficulty concentrating, and thoughts of death.

Depression can be a one-time occurrence but is often an ongoing problem throughout a person's lifetime. A total of 15% of patients with major depressive disorders die of suicide. The onset of depression is often linked to environmental factors such as life events that greatly increase stress. Despite this association, depression has a strong genetic component. Genetics accounts for 40%–50% of the risk for depression in a person's lifetime, and the risk for members of a family does not change if the members are raised separately.

We are using cell-based screening technology and a mouse model to identify the genes and pathways that contribute to depressive behavior. Currently, we are conducting a survey in 30 strains of mice for differences in molecular, biochemical, and behavioral traits that represent endophenotypes (i.e., single well-defined symptoms or traits of a much more complex disorder) associated with depression. In cataloging the variation in quantities of neurotransmitters and stress hormones in the blood, gene expression in regions of the brain such as the hippocampus and hypothalamus, and performance in behavioral models such as the tail suspension test and open field test, we are producing the data necessary to identify the genetic controls for each of these traits. Using the in silico genetic mapping method, we can correlate the natural variation of these measurements present in the inbred lines of mice with the underlying haplotype structure of the mice, thereby pinpointing biologically important genes.

In parallel, we are developing a cell-based assay to monitor the function of the serotonin transporter, the gene target of the most common pharmaceutical treatment for depression: selective serotonin reuptake inhibitors. Using this assay, we can screen the 14,500 full-length clone cDNA library of Scripps Florida for genes that modify the function of the transporter. Additionally, introducing a selective serotonin reuptake inhibitor to the screen will enable us to identify genes that modulate the efficacy of this important class of drugs. Cumulatively, we hope to provide a better understanding of the molecular basis of depression and its treatment to allow for improved diagnosis and therapies.


Miller, B.H., Schultz, L.E., Gulati, A., Cameron, M.D., Pletcher, M.T. Genetic regulation of behavioral and neuronal responses to fluoxetine. Neuropsychopharmacology, in press.

Pinto, L.H., Vitaterna, M.H., Shimomura, K., Siepka, S.M., Balannik, V., McDearmon, E.L., Omura, C., Lumayag, S., Invergo, B.M., Glawe, B., Cantrell, D.R., Inayat, S., Olvera, M.A., Vessey, K.A., McCall, M.A., Maddox, D., Morgans, C.W., Young, B., Pletcher, M.T., Mullins, R.F., Troy, J.B., Takahashi, J.S. Generation, identification and functional characterization of the nob4 mutation of Grm6 in the mouse. Vis. Neurosci. 24:111, 2007.


Mathew T. Pletcher, Ph.D.
Assistant Professor
Florida Campus

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