Interim Chair of Department of Neurosciences
Department of Neurosciences
Case Western Reserve University
School of Medicine
Research in the Deneris lab is aimed at understanding the genetic mechanisms that act across the lifespan to regulate serotonin system function and to determine how these mechanisms impact serotonin modulated behaviors. Our studies have identified transcription factors that function in an embryonic regulatory network to specify serotonin neurons in the mouse ventral hindbrain.
Current research in the lab is focussed 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 new 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.
Htr1A and Htr1B Autoregulatory Pathways
Ongoing Pet-1 expression is required after serotonergic neurogenesis for induction of the autoregulatory receptors that control 5HT neuron firing and transmitter release.
Whole cell recordings in YFP-marked, conditionally targeted Pet-1 mutant 5HT neurons shows an absence of 5HT 1A agonist responses.
Induction of 5HT 1A and 5HT 1B receptor gene expression, which normally occurs around E15, fails in conditionally targeted Pet-1 mutant mice.
We have developed new genetic-based approaches to investigate the physiological importance of serotonin system function. These approaches rely on BAC transgenic tools that were made possible by the identification of the Pet-1 cis regulatory region that directs highly reproducible expression of transgenes in developing and adult brain 5HT neurons. These tools have enabled the genetic marking of brain 5HT neurons for whole cell patch clamp recordings and purification of these neurons by FACS. They have also allowed us to target gene expression specifically in 5HT neurons at any stage of life. Our new approaches have resulted in a series of published studies that demonstrated that disruption of the transcription regulatory network that governs serotonergic neurogenesis is a potential mechanism for behavioral pathogenesis as alterations in the network cause dramatic abnormalities in emotional behaviors, maternal behavior, inflammatory pain, respiratory system maturation and thermoregulation.
Future studies are aimed at determining the importance Pet-1-dependent transcription in the early postnatal critical period for adult antipsychotic drug responses, maternal behavior and chronic stress and to use deep sequencing approaches to determine the mechanisms of Pet-1 function in serotonin neurons.