Serotonergic gene expression and depression: implications for developing novel antidepressants

The development and configuration of several neural networks is dependent o n the actions of serotonin (5-HT) acting through multiple hetero- and autor eceptor subtypes. During early brain development 5-HT modulates morphogenet ic activities, such as neural differentiation, axon outgrowth, and synaptic modeling. In the adult brain, midbrain raphe: serotonergic neurons project to a variety of brain regions and modulate a wide range of physiological f unctions. Several lines of evidence indicate that genetically determined va riability in serotonergic gene expression, as it has been documented for th e 5-HT transporter, influences temperamental traits and may lead to psychop athological conditions with increased anxiety, depression, and aggression. Investigation of the regulation of serotonergic gene transcription and its impact on neuronal development, synaptic plasticity, and neurogenesis spur interest to identify serotonergic gene-related molecular factors underlying disease states and to develop more effective antidepressant treatment stra tegies. Gene targeting strategics have increasingly been integrated into in vestigations of brain function and along with the fading dogma of a limited capacity of neurons for regeneration and reproducibility, it is realized t hat gene transfer techniques using efficient viral vectors in conjunction w ith neuron-selective transcriptional control systems may also be applicable to complex disorders of the brain. Given the fact that the 5-HT system con tinues to be an important target for drug development and production, novel strategies aiming toward the modification of 5-HT function at the level of gene expression are likely to be exploited by enterprises participating ac tively in the introduction of alternative therapeutic approaches. (C) 2001 Elsevier Science B.V. All rights reserved.