Serotonergic gene expression and depression: implications for developing novel antidepressants

The development and configuration of several neural networks is dependent on the actions of serotonin (5-HT) acting through multiple hetero- and autoreceptor subtypes. During early brain development 5-HT modulates morphogenetic 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 functions. Several lines of evidence indicate that genetically determined variability in serotonergic gene expression, as it has been documented for the 5-HT transporter, influences temperamental traits and may lead to psychopathological 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 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 and reproducibility, 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 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.