Serotonergic gene transcriptional control regions: Targets for antidepressant drug development?

Abstract

The formation and integration of neural networks is dependent on the actions of the master control neurotransmitter serotonin (5-HT) acting through multiple 5-HT receptor subtypes. During brain development 5-HT regulates morphogenetic activities, such as neural differentiation, axon outgrowth, and configuration of synaptic connections. In the adult brain, midbrain raphe serotonergic neurons project to a variety of brain regions and modulate a wide range of physiological functions. Several lines of evidence indicate that genetically determined variability in serotonergic gene expression influences complex behaviour and may lead to conditions with increased anxiety, depression, and aggression. Investigation of the regulation of serotonergic gene transcription and its impact on neural development and plasticity will spur general interest to identify serotonergic gene-related molecular factors underlying disease states and to develop more effective treatment strategies. Gene targeting strategies have increasingly been integrated into investigations of brain function and along with the fading dogma of a limited capacity of neurons for regeneration, reproducibility, and plasticity, it is realized that gene transfer techniques using efficient viral vectors in conjunction with neuron-selective transcriptional control systems may also be applicable to complex disorders of the brain. Given the fact that the 5-HT system continues to be an important target for large-scale 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 actively in the introduction of alternative therapeutic approaches.