Autism spectrum disorder (ASD) emerges before the age of three and is defined by social dysfunction, communication deficits, and repetitive behaviors. Current treatments show limited evidence of benefit for core ASD symptoms. We need new treatments based upon an understanding of pathophysiology. Twin studies identify ASD as the most heritable behaviorally defined disorder. The most robust ASD biomarker is elevated whole blood serotonin (5-HT), or hyperserotonemia, present in more than 25% of children with ASD. Genetic linkage and association studies point to the serotonin transporter (SERT) gene in both ASD and obsessive compulsive disorder (OCD), which share the core symptom of repetitive behavior. Rare SERT variants are associated with rigid-compulsive behavior in ASD and have also been identified in OCD families. We have developed a mouse that expresses the most common of these variants, SERT Ala56. This mouse recapitulates the elevated whole blood 5-HT biomarker and shows increased brain 5-HT clearance and 5-HT receptor sensitivity. The SERT Ala56 mouse also shows altered social behavior and a novel repetitive wireclimbing/ hanging behavior. Rather than consider this mouse as a model of ASD as a category, we propose to focus on behavioral domains, considering alterations in response to social stimuli separately from repetitive behaviors. As in other models of ASD susceptibility, further work is needed to connect neuronal changes and resulting behaviors. To match the behavioral phenotypes to underlying circuitry and molecular disturbances, we will use developmental and gene expression approaches. First, we will assess the developmental impact of increased SERT function on different brain regions. Second, we will map neuronal activation patterns by immediate early gene expression (cFos) in response to behavioral challenge with social stimuli or during repetitive behavior. Third, we will identify downstream transcriptome changes in the key brain regions implicated by developmental and behavioral challenge experiments. Finally, we will examine the causal relationship between gene expression changes and altered behaviors. The results will provide a window into ASD susceptibility in the large group of children with the hyperserotonemia endophenotype, and they will also impact our understanding of other disorders that affect these behavioral domains, such as social phobia or OCD. The ultimate goal is to expand studies of these neurobiological signatures to reveal new options for treatment of social dysfunction and repetitive behavior.

Public Health Relevance

Rare, functional variants in the serotonin transporter (SERT) are associated with autism and rigid-compulsive behavior. We have identified altered social function and repetitive behavior in a transgenic mouse expressing the most common of these variants, SERT Ala56. Here we propose to use convergent developmental and gene expression approaches to identify brain regions and genes that mediate these core behavioral deficits.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH094604-04
Application #
8660333
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Nadler, Laurie S
Project Start
2011-07-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Veenstra-VanderWeele, Jeremy (2017) Translation in fragile X: no home runs in the first at-bat. J Neurodev Disord 9:21
Margolis, Kara Gross; Li, Zhishan; Stevanovic, Korey et al. (2016) Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function. J Clin Invest 126:2221-35
Nackenoff, Alex G; Moussa-Tooks, Alexandra B; McMeekin, Austin M et al. (2016) Essential Contributions of Serotonin Transporter Inhibition to the Acute and Chronic Actions of Fluoxetine and Citalopram in the SERT Met172 Mouse. Neuropsychopharmacology 41:1733-41

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