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Scientific Report 2007
Scripps Florida
Biochemistry
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.
Publications
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.
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