This application proposes to continue research into the transcriptional mechanisms that control development of serotonin (5ht) neuron transmitter traits and 5ht-modulated behaviors. Altered 5ht signaling has been implicated in the pathogenesis of numerous neurological and psychiatric disorders such as autism, sudden infant death syndrome (SIDS), depression, and anxiety. Many of these disorders are neurodevelopmental in origin and risk for acquiring them is influenced by heritable susceptibility factors. Thus, the general concept that stimulates the research proposed here is that genetically driven variation in transcriptional programs governing 5ht neuron development contributes to the pathogenesis of certain neurological and psychiatric disorders by adversely altering 5ht system activity. The focus of the proposed research is the Pet-1 ETS factor whose expression is initiated specifically in postmitotic 5ht neuron precursors before the appearance of 5ht and then maintained in all adult 5ht neurons. Loss of functions studies in the mouse demonstrated that Pet-1 is a critical transcriptional determinant of 5ht neuron phenotype and 5ht-modulated behaviors. These findings support the existence of a Pet-1 dependent transcriptional program that impacts 5ht- modulated behaviors through its control of embryonic 5ht neuron development. The new aims proposed here will address the following questions: 1) Is the FEV ETS factor the functional human orthologue of Pet-1 and does a FEV-dependent genetic program govern human 5ht neuron development? 2) Does the level of Pet- 1/FEV activity determine the level of 5ht neuron transmitter traits and 5ht neuron function? 3) What role does Pet-1 play in mature 5ht neurons? 4) Is the transcriptional control of Pet-1 and FEV conserved? The proposed aims will be investigated with molecular genetic approaches and will be greatly facilitated by our newly developed genetic based tools designed to access 5ht neurons, in vivo. If FEV functions in human 5ht neuron development then alterations in FEV activity brought about either by genetic or environmental factors are a potential source of risk for psychiatric or neurological disease and interindividual variation in behavior. The proposed studies are likely to have a long-term impact on molecular psychiatry research by advancing an understanding of the genetic mechanisms that govern 5ht neuron development and determining how these mechanisms impact behavior and physiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH062723-10
Application #
7754642
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Panchision, David M
Project Start
2000-12-01
Project End
2011-06-30
Budget Start
2010-01-01
Budget End
2011-06-30
Support Year
10
Fiscal Year
2010
Total Cost
$318,792
Indirect Cost
Name
Case Western Reserve University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Wyler, Steven C; Donovan, Lauren J; Yeager, Mia et al. (2015) Pet-1 Controls Tetrahydrobiopterin Pathway and Slc22a3 Transporter Genes in Serotonin Neurons. ACS Chem Neurosci 6:1198-205
Issler, Orna; Haramati, Sharon; Paul, Evan D et al. (2014) MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity. Neuron 83:344-360
Spoida, Katharina; Masseck, Olivia A; Deneris, Evan S et al. (2014) Gq/5-HT2c receptor signals activate a local GABAergic inhibitory feedback circuit to modulate serotonergic firing and anxiety in mice. Proc Natl Acad Sci U S A 111:6479-84
Ciarleglio, Christopher M; Resuehr, Holly E S; Axley, John C et al. (2014) Pet-1 deficiency alters the circadian clock and its temporal organization of behavior. PLoS One 9:e97412
Deneris, Evan S; Hobert, Oliver (2014) Maintenance of postmitotic neuronal cell identity. Nat Neurosci 17:899-907
Deneris, Evan S; Wyler, Steven C (2012) Serotonergic transcriptional networks and potential importance to mental health. Nat Neurosci 15:519-27

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