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.

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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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZMH1)
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Nadler, Laurie S
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Vanderbilt University Medical Center
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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
Muller, C L; Anacker, A M J; Veenstra-VanderWeele, J (2016) The serotonin system in autism spectrum disorder: From biomarker to animal models. Neuroscience 321:24-41
Schauder, Kimberly B; Muller, Christopher L; Veenstra-VanderWeele, Jeremy et al. (2015) Genetic Variation in Serotonin Transporter Modulates Tactile Hyperresponsiveness in ASD. Res Autism Spectr Disord 10:93-100
Veenstra-VanderWeele, Jeremy; Warren, Zachary (2015) Intervention in the context of development: pathways toward new treatments. Neuropsychopharmacology 40:225-37
McGuire, Kelly; Shui, Amy M; Veenstra-VanderWeele, Jeremy (2015) Clinical Correlates of Early Generalized Overgrowth in Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry 54:957-8
Peters, Brittany; Williams, Kent C; Gorrindo, Phillip et al. (2014) Rigid-compulsive behaviors are associated with mixed bowel symptoms in autism spectrum disorder. J Autism Dev Disord 44:1425-32
Kerr, Travis M; Muller, Christopher L; Miah, Mahfuzur et al. (2013) Genetic background modulates phenotypes of serotonin transporter Ala56 knock-in mice. Mol Autism 4:35
Veenstra-Vanderweele, Jeremy (2013) Here/in this issue and there/abstract thinking: human brain development in a dish. J Am Acad Child Adolesc Psychiatry 52:993-4
Veenstra-Vanderweele, Jeremy (2013) In this issue/abstract thinking: genetic testing in neurodevelopmental disorders. J Am Acad Child Adolesc Psychiatry 52:449-50
Veenstra-VanderWeele, Jeremy; Blakely, Randy D (2012) Networking in autism: leveraging genetic, biomarker and model system findings in the search for new treatments. Neuropsychopharmacology 37:196-212

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