Altered levels of serotonergic activity have been linked to the pathogenesis of numerous neurological and psychiatric disorders such as autism, sudden infant death syndrome (SIDS), depression, and anxiety. These alterations are thought to cause abnormal formation of neural circuitry responsible for the development and expression of adaptive behaviors and physiological processes. How might these alterations be brought about? Genetic variation in or near genes encoding the serotonin (5-HT) reuptake transporter, 5-HT1A receptor, and the rate-limiting synthetic enzyme tryptophan hydroxylase 2 is associated with risk for behavioral pathogenesis (Holmes, 2008). Functional studies in cell culture suggest that some of the identified variants alter levels of gene transcription.

These findings raise an alternative potential mechanism underlying behavioral pathogenesis in which variation in serotonergic gene transcription causes altered levels of serotonergic activity. As many of the disorders in which serotonergic dysfunction has been implicated are neurodevelopmental in origin, altered function of the transcriptional programs that control 5-HT neuron generation may establish a vulnerability for pathogenesis by directing abnormal levels of serotonergic signaling that in turn disrupt neural circuit formation during critical periods in early life.

Over the past decade, transcriptional cascades that program the generation of 5-HT neurons have been identified. Gene targeting of individual cascade factors has created specific deficiencies in serotonergic transcription at a stage when CNS neural circuitry has not yet formed (Hendricks et al, 2003; Zhao et al, 2006). These studies show that all of the cascade factors are necessary for the initiation of 5-HT synthesis. Furthermore, rescue experiments in cascade-disrupted mice show that the level of serotonergic function is sensitive to the level of expression of the transcriptional program that gives rise to 5-HT neurons (Lerch-Haner et al, 2008).

The irreversible alterations in brain serotonergic transcription are not lethal and therefore cascade-targeted mice provide a new way to investigate the impact of altered serotonergic function on animal behaviors and physiological processes that are relevant to many psychiatric and neurological disorders. Indeed, disruption of the serotonergic transcriptional cascade causes alterations in emotional behaviors (Hendricks et al, 2003). In addition, these approaches have provided experimental support, in vivo, for the hypothesis that abnormal serotonergic development contributes to SIDS vulnerability (Erickson et al, 2007; Hodges et al, 2008). They have also revealed maternal nurturing as a previously unrecognized 5-HT system-modulated behavior (Lerch-Haner et al, 2008). The accompanying high mortality rate of offspring born to cascade-targeted mothers forces a reassessment of the long-held view that the brain 5-HT system is not essential for physiological processes and animal survival.

The new genetic approaches created to study 5-HT neuron development and function support the idea that altered transcriptional programming of serotonergic signaling is a potential mechanism underlying behavioral and physiological pathogenesis. Future studies might be focused on determining the vulnerability of cascade activity to fetal and early postnatal exposure to environmental insults such as drugs and harmful stress. In addition, the identification of genetic variation that impacts cascade factor activity may reveal additional 5-HT-related risk factors for pathogenesis beyond the usual suspects.