Presynaptic, serotonin (5-hydroxytryptamine, 5-HT) transporters (SERTs) limit the signaling potential of 5-HT and recycle 5-HT for further release. SERTs are targets for antidepressants and psychostimulants. Altered SERT expression and function may contribute to multiple neuropsychiatric disorders, including anxiety, OCD, depression and suicide. The majority of studies that explore the contribution of SERT to mental illness have focused on disorders of adult onset. However, increasing evidence demonstrates that 5-HT signaling in the developing brain is critical to establish normal connectivity and behavior and. A key example, autism spectrum disorder (ASD), has been linked to abnormal 5-HT homeostasis for 50 years. The Blakely lab identified and characterized five rare, functional SERT coding variants in ASD subjects, all of which display enhanced 5-HT transport capacity. Blakely's team has developed a transgenic (knock-in) mouse expressing the most common of the ASD SERT variants, Gly56Ala. SERT Ala56 mice display hyperserotonemia and multiple behavioral phenotypes that support the SERT Ala56 model as a powerful platform to understand how compromised 5-HT signaling during development can generate lifelong behavioral deficits. Efforts to capture this opportunity are embraced by Project 3: Modeling the Serotonin Contribution to Autism Spectrum Disorders, In Specific Aim I, Blakely capitalizes on powerful RNA sequencing approaches to elucidate transcriptional networks impacted by SERT Ala56 in raphe neurons, placental tissues and B cells of the immune system.
In Specific Aim II, Blakely seeks to reverse phenotypes associated with SERT Ala56 expression using 5-HT receptor agonists and other molecules suggested from gene network alterations.
In Specific Aim III, Blakely's group develops novel, transgenic mouse models that provides for conditional expression of the SERT 56Ala variant, with the goal of understanding the contribution of specific sites and timing of SERT Ala56 expression to the phenotypes found in mice and humans harboring this variant.

Public Health Relevance

Autism Spectrum Disorder (ASD) is increasingly realized to be much more prevalent than previously believed. Our research focuses on a newly developed animal model carrying an ASD-associated gene variant in the serotonin transporter (SERT), SERT Ala56. SERT is responsible for inactivating serotonin in the brain and periphery and we suspect that altered availability of serotonin contributes to multiple components of ASD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
1P50MH096972-01
Application #
8470382
Study Section
Special Emphasis Panel (ZMH1-ERB-S (02))
Project Start
Project End
Budget Start
2012-08-22
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$236,532
Indirect Cost
$84,909
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Knoll, A T; Jiang, K; Levitt, P (2018) Quantitative trait locus mapping and analysis of heritable variation in affiliative social behavior and co-occurring traits. Genes Brain Behav 17:e12431
Deneris, Evan; Gaspar, Patricia (2018) Serotonin neuron development: shaping molecular and structural identities. Wiley Interdiscip Rev Dev Biol 7:
Stewart, Adele; Davis, Gwynne L; Gresch, Paul J et al. (2018) Serotonin transporter inhibition and 5-HT2C receptor activation drive loss of cocaine-induced locomotor activation in DAT Val559 mice. Neuropsychopharmacology :
Mayer, Felix P; Schmid, Diethart; Owens, W Anthony et al. (2018) An unsuspected role for organic cation transporter 3 in the actions of amphetamine. Neuropsychopharmacology 43:2408-2417
Robson, Matthew J; Quinlan, Meagan A; Margolis, Kara Gross et al. (2018) p38? MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse. Proc Natl Acad Sci U S A 115:E10245-E10254
Brindley, Rebecca L; Bauer, Mary Beth; Walker, L Anne et al. (2018) Adrenal serotonin derives from accumulation by the antidepressant-sensitive serotonin transporter. Pharmacol Res :
Ritter, K Elaine; Wang, Zunyi; Vezina, Chad M et al. (2017) Serotonin Receptor 5-HT3A Affects Development of Bladder Innervation and Urinary Bladder Function. Front Neurosci 11:690
Kast, Ryan J; Wu, Hsiao-Huei; Williams, Piper et al. (2017) Specific Connectivity and Unique Molecular Identity of MET Receptor Tyrosine Kinase Expressing Serotonergic Neurons in the Caudal Dorsal Raphe Nuclei. ACS Chem Neurosci 8:1053-1064
O'Neil, Richard T; Wang, Xiaojing; Morabito, Michael V et al. (2017) Comparative analysis of A-to-I editing in human and non-human primate brains reveals conserved patterns and context-dependent regulation of RNA editing. Mol Brain 10:11
Sharif, N F; Korade, Z; Porter, N A et al. (2017) Oxidative stress, serotonergic changes and decreased ultrasonic vocalizations in a mouse model of Smith-Lemli-Opitz syndrome. Genes Brain Behav 16:619-626

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