PHARMACOLOGICAL ACTIONS OF ANTIDEPRESSANT TREATMENTS

University Of Texas Sw Med Ctr/Dallas, Dallas TX

Investigators

Linked publications & trials

Abstract

DESCRIPTION (from applicant's abstract): Significant progress was made in the previous grant period in identifying signal transduction proteins in the brain that are altered by chronic antidepressant treatments. In the next grant period, we propose to considerably focus our attention on a subset of these adaptations, which will be characterized mechanistically in considerable depth. The major objective of this proposal is to explore the role of novel isoforms of the transcription factor" deltaFosB, in mediating the long-term actions of antidepressant treatments in brain. Previous work supported by this grant has established that chronic, but not acute, administration of several classes of antidepressants induces the deltaFosB isoforms in specific brain regions, particularly superficial layers of prefrontal cortex. DeltaFosB, due to its extraordinary stability, persists in brain for weeks after discontinuation of these treatments. Thus, induction of deltaFosB provides an attractive molecular mechanism for the delayed yet persistent changes in gene expression caused by chronic antidepressant exposure. The proposed studies win focus on specific glutamate receptor subunits as possible physiological targets for deltaFosB. We have found that antidepressant regulation of certain subunits, seen in superficial layers of prefrontal cortex of rats and wildtype mice, is abolished in fosB knockout mice. In addition, by use of inducible transgenic nuce recently developed in our laboratory, we have shown that overexpression of deltaFosB in prefrontal cortex mimics antidepressant regulation of these receptor subunits. Finally, the promoters of the genes for these regulated receptor subunits contain AP-1 sites (the DNA targets for AFosB) and are regulated upon overexpression of deltaFosB in cultured cells and neurons. Together, this work will establish deltaFosB as both a necessary and sufficient mediator of antidepressant regulation of glutamate receptor expression in the brain. Such regulation could contribute to the beneficial effects of these treatments in humans based on indirect evidence that has implicated glutamatergic transmission in antidepressant action. More fundamentally, however, the proposed studies will improve our general understanding of the precise molecular mechanisms that control the expression of glutamate receptors, key mediators of synaptic transmission, in the brain.