The serotonin (5-hydroxytryptamine, 5-HT) system is a neurotransmitter system that plays a critical role in neuromodulation. This exceedingly small population of neurons sends an impressively expansive network of axons that beautifully innervate nearly all areas of the brain and spinal cord. Unsurprisingly, serotonin modulates nearly all behaviors and physiological functions, and its system dysfunction has been implicated in numerous neuropsychiatric disorders including depression, anxiety, schizophrenia, post traumatic stress disorder, obsessive compulsive disorder, and others. A widely discussed hypothesis is that altered gene expression or dysfunction of the serotonin gene regulatory networks (GRNs) that control genes involved the biosythesis, transport, signaling, reuptake or metabolism of serotonin, resulting in neurotransmitter levels which are either too high or too low and increase susceptibility to neuropsychiatric illness.
Research in the lab is focused on using a recently developed temporally controlled genetic targeting approach to investigate the requirement for ongoing serotonergic transcription in serotonin system maturation and maintenance across the lifespan. Our findings have shown that, Pet1, a key factor in the serotonergic specification network, continues to function at subsequent stages of serotonin system maturation to regulate serotonergic axonal innervation patterns and acquisition of intrinsic autoregulatory pathways that modulate serotonin neuron firing and transmitter release. Pet1-dependent transcription is still needed in adult serotonin neurons to directly regulate brain serotonin synthesis and reuptake and to maintain emotional behaviors. These findings demonstrate that alterations in serotonergic transcriptional networks at any stage of life can disrupt serotonin system modulation of behavior and physiology. Our genetic tools allow ongoing projects to explore the consequences loss of critical transcription factors Pet1 and Lmx1b have on serotonin neuron ingerity and functional states at various life stages.