Combining genetic and genomic
approaches to study mood disorders

Sibille E, Hen R.
Center for Neurobiology and Behavior,
Columbia University, 722 W. 168th St., PI Annex 731,
New York, NY 10032, USA.
Eur Neuropsychopharmacol 2001 Dec;11(6):413-21


Recent technological advances in genetic manipulations and DNA microarrays are profoundly altering the landscape of biological research, offering opportunities to investigate biological questions that were only dreamed of a few years ago. With this revolution comes the hope of being able to tackle some of the more arduous challenges that the central nervous system has presented to the research community. Specifically, a major goal in the study of neuropsychiatric disorders has been to identify underlying mechanisms of brain dysfunction with the expectation that these insights may allow a better diagnosis, prevention and effective treatments for these disorders. For the most part, treatments of these disorders have relied on serendipitous discovery of pharmacological entities with therapeutic efficacy, while the causes of the disorders have remained unknown. The serotonin system, and the serotonin(1A) (5-HT(1A)) receptor in particular, have been under intense investigation, mostly due to the fact that serotonergic drugs that directly or indirectly affect the 5-HT(1A) receptor, are effective therapeutic agents in treating patients with various neuropsychiatric disorders, including anxiety and depression. Genetic deletion of the receptor in mouse results in increased anxiety, thus supporting an active role for this receptor in mood regulation. However, the analysis of genetic deletion experiments can be confounded by hidden developmental roles of the missing receptor, by adaptive compensatory mechanisms, as well by the fact that the genes or gene products that are responsible for the cellular and molecular aspects of the phenotype may be several steps removed from the genetic intervention. Here, we present a combined methodological approach of tissue specific and conditional genetic manipulations, with large-scale search for altered gene expression, as an experimental framework to investigate the role of genes with complex functions and/or complex expression patterns. The 5-HT(1A) receptor is used as a model of gene product with complex functions and distributions, and as a prototypical system to which these new genetic approaches are currently being applied.
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