it is possible that the 5-HT in our brains plays an essential part in keeping us sane..
— Sir John Gaddum on LSD, (The Day Tripper) 1954

Research

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 and neurodevelopmental disorders including depression, anxiety, schizophrenia, post traumatic stress disorder, obsessive compulsive disorder, and others.  The prevailing theory suggests that at the genetic level a predisposition paired with environmental stresses can causes dysregulation 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 result in pathology. 

5ht hypoth.png
Serotonergic–type neuron identity 5–HT neurons coexpress a gene battery encoding 5–HT synthetic (Tph2, Aadc, Gch1, Gfrp, Ptps, Qdpr), reuptake (Sert), vesicular transport (Vmat2), autoreceptor signaling (Htr1a, Htr1b) and metabolism (Maoa, Maob) proteins. Tetrahydrobiopterin (BH4), an essential cofactor for Tph2 in the synthesis of 5–HTP, is synthesized (red pathway) de novo from guanosine triphosphate (GTP). It is also recycled through a regeneration pathway (brown). Aldehyde dehydrogenase (Aldh) converts 5–Hydroxyindolealdehyde into 5–Hydroxyindoleacetic acid (5–HIAA). Following release, 5–HT modulates 5–HT neuron firing through somatodendritic Htr1a autoreceptors, 5–HT release from the pre–synaptic terminal through Htr1b autoreceptors and stimulates neurotransmission through post–synaptic 5–HT receptors (5–HT1–7). 

Serotonergic–type neuron identity

5–HT neurons coexpress a gene battery encoding 5–HT synthetic (Tph2AadcGch1GfrpPtpsQdpr), reuptake (Sert), vesicular transport (Vmat2), autoreceptor signaling (Htr1a, Htr1b) and metabolism (MaoaMaob) proteins. Tetrahydrobiopterin (BH4), an essential cofactor for Tph2 in the synthesis of 5–HTP, is synthesized (red pathway) de novo from guanosine triphosphate (GTP). It is also recycled through a regeneration pathway (brown). Aldehyde dehydrogenase (Aldh) converts 5–Hydroxyindolealdehyde into 5–Hydroxyindoleacetic acid (5–HIAA). Following release, 5–HT modulates 5–HT neuron firing through somatodendritic Htr1a autoreceptors, 5–HT release from the pre–synaptic terminal through Htr1b autoreceptors and stimulates neurotransmission through post–synaptic 5–HT receptors (5–HT1–7). 

5-HT neuron gene regulatory networks. Depicted regulatory interactions (arrows) at the indicated stages of life are based on germ line or conditional loss of function data for each indicated TF. Terminal effector genes are depicted in rectangles and transcription factors in ovals. 5-HT pathway genes encoding 5-HT synthesis (Tph2, Ddc, Gch1, Qdpr), reuptake (Slc6a4, Slc22a3), vesicular transport (Slc18a2), and metabolism (Maoa, Maob) are shown in rectangles with black letters. Terminal effector genes depicted in blue letters (Gria4, Htr1a, Htr1b, Adra1b, Lpar1, Hcrtr1) encode AMPA receptor subunit GLUR4 and GPCRs required for responses to diverse synaptic inputs.

5-HT neuron gene regulatory networks. Depicted regulatory interactions (arrows) at the indicated stages of life are based on germ line or conditional loss of function data for each indicated TF. Terminal effector genes are depicted in rectangles and transcription factors in ovals. 5-HT pathway genes encoding 5-HT synthesis (Tph2, Ddc, Gch1, Qdpr), reuptake (Slc6a4, Slc22a3), vesicular transport (Slc18a2), and metabolism (Maoa, Maob) are shown in rectangles with black letters. Terminal effector genes depicted in blue letters (Gria4, Htr1a, Htr1b, Adra1b, Lpar1, Hcrtr1) encode AMPA receptor subunit GLUR4 and GPCRs required for responses to diverse synaptic inputs.

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, Pet-1, 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. Pet-1-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 Pet-1 and Lmx1b have on serotonin neuron integrity and functional states at various life stages.