Numerous clinical reports have associated the use of the acne drug Accutane (Isotretinoin, 1 3-cis retinoic acid, RA) with depression. However, the precise behavioral effects of RA are unknown because few studies have investigated the neurological effects of RA. RA enters the CNS and is a potent transcriptional activator and thus it is highly likely that RA will influence brain function. One of the few areas of the adult brain in which RA function has been investigated is the hippocampus where RA is required for learning and memory. These processes probably require new neuronal birth in the hippocampus and RA may be linked via its influence as a powerful inducer of neural stem cell differentiation. A new hypothesis for the underlying cause of human depression is a decline in the birth of new neurons in the hippocampus. Chronic exposure to RA would be expected to cause exactly that by persistently inducing neuronal differentiation and eventually depleting the neural stem cells that generate neurons. The goal will be to test this hypothesis by investigating the influence of RA on cell division in the hippocampus as measured by 5-bromo deoxy-uridine (BrdU) incorporation into cells double labeled for either neuronal or glial cell markers. This will be correlated with hippocampal dependant and independent behavioral changes in these animals. We predict that treatment with RA will result in a decrease in hippocampal neurogensis in mice and will result in degradation of hippocampal dependant behavior. These studies will lead to future studies on 1) the normal function of RA in hippocampal neurogenesis, 2) the role of neurogenesis in behavior changes and, most importantly 3) the neurological consequences of Accutane treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH066037-02
Application #
6658199
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Sieber, Beth-Anne
Project Start
2002-09-09
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2003
Total Cost
$140,700
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Crandall, James; Sakai, Yasuo; Zhang, Jinghua et al. (2004) 13-cis-retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice. Proc Natl Acad Sci U S A 101:5111-6
Mey, Jorg; McCaffery, Peter (2004) Retinoic acid signaling in the nervous system of adult vertebrates. Neuroscientist 10:409-21
McCaffery, P J; Adams, J; Maden, M et al. (2003) Too much of a good thing: retinoic acid as an endogenous regulator of neural differentiation and exogenous teratogen. Eur J Neurosci 18:457-72