Cited by 333Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersNeurotransmitter Receptor Influence on Behavior

Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior

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Veenstra-VanderWeele, Jeremy, Muller, Christopher L., Iwamoto, Hideki, Sauer, Jennifer E., Owens, W. Anthony, Shah, Charisma R., Cohen, Jordan, Mannangatti, Padmanabhan +12 more·2012·Proceedings of the National Academy of Sciences

Abstract

Fifty years ago, increased whole-blood serotonin levels, or hyperserotonemia, first linked disrupted 5-HT homeostasis to Autism Spectrum Disorders (ASDs). The 5-HT transporter (SERT) gene ( SLC6A4 ) has been associated with whole blood 5-HT levels and ASD susceptibility. Previously, we identified multiple gain-of-function SERT coding variants in children with ASD. Here we establish that transgenic mice expressing the most common of these variants, SERT Ala56, exhibit elevated, p38 MAPK-dependent transporter phosphorylation, enhanced 5-HT clearance rates and hyperserotonemia. These effects are accompanied by altered basal firing of raphe 5-HT neurons, as well as 5HT 1A and 5HT 2A receptor hypersensitivity. Strikingly, SERT Ala56 mice display alterations in social function, communication, and repetitive behavior. Our efforts provide strong support for the hypothesis that altered 5-HT homeostasis can impact risk for ASD traits and provide a model with construct and face validity that can support further analysis of ASD mechanisms and potentially novel treatments.

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Authors
Veenstra-VanderWeele, J., Muller, C. L., Iwamoto, H., Sauer, J. E., Owens, W. A., Shah, C. R., Cohen, J., Mannangatti, P., Jessen, T., Thompson, B. J., Ye, R., Kerr, T. M., Carneiro, A. M., Crawley, J. N., Sanders-Bush, E., McMahon, D. G., Ramamoorthy, S., Daws, L. C., Sutcliffe, J. S., & Blakely, R. D.
Affiliations
  • Vanderbilt University (US)
  • The University of Texas at San Antonio Health Science Center (US)
  • National Institutes of Health (US)
  • Departments of aPsychiatry,
Venue
Proceedings of the National Academy of Sciences
Published
2012-03-19
Volume
109
Issue
14
Pages
5469-5474
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2104220482
Cited by
333
References
76
Citations by year
2026: 11 · 2025: 9 · 2024: 18 · 2023: 17 · 2022: 21 · 2021: 26 · 2020: 20 · 2019: 25 · 2018: 23 · 2017: 27 · 2016: 33 · 2015: 23 · 2014: 29 · 2013: 33 · 2012: 18
FWCI
16.85
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Autism Speaks (AS2429)
  • Vanderbilt University (HD15052)
  • Vanderbilt Institute for Clinical and Translational Research (RR024975)
  • H. Lundbeck A/S
  • National Institutes of Health (HD-15052, RR024975)
  • Vanderbilt Kennedy Center, Vanderbilt University Medical Center
  • National Institute of Mental Health (R01MH094527, K08MH081066, MH081066, MH078098, R01MH062612, MH094604, MH-62612, R01MH094604, R03MH078098)
  • National Institute on Drug Abuse (DA-07390, R01DA007390)
  • National Center for Research Resources (RR024975, KL2RR024977, TL1RR024978, UL1RR024975)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD015052, HD 15052, HD065278, R01HD065278)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
autism spectrum disorder, hyperserotonemia, serotonin transporter, gain-of-function mutations, p38 MAPK, serotonin clearance, raphe neurons, 5-HT1A receptor, 5-HT2A receptor, receptor hypersensitivity, social dysfunction, repetitive behavior, transgenic mouse model
MeSH terms
Animals, Autistic Disorder, Disease Models, Animal, Homeostasis, Receptors, Serotonin, Serotonin, Social Behavior, Stereotyped Behavior, Mice

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