TY - JOUR
T1 - Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior
AU - Veenstra-VanderWeele, Jeremy
AU - Muller, Christopher L.
AU - Iwamoto, Hideki
AU - Sauer, Jennifer E.
AU - Owens, W. Anthony
AU - Shah, Charisma R.
AU - Cohen, Jordan
AU - Mannangatti, Padmanabhan
AU - Jessen, Tammy
AU - Thompson, Brent J.
AU - Ye, Ran
AU - Kerr, Travis M.
AU - Carneiro, Ana M.
AU - Crawley, Jacqueline N.
AU - Sanders-Bush, Elaine
AU - McMahon, Douglas G.
AU - Ramamoorthy, Sammanda
AU - Daws, Lynette C.
AU - Sutcliffe, James S.
AU - Blakely, Randy D.
PY - 2012/4/3
Y1 - 2012/4/3
N2 - 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.
AB - 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.
KW - Development
KW - Monoamine
KW - Neurotransmitter
UR - http://www.scopus.com/inward/record.url?scp=84859475819&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859475819&partnerID=8YFLogxK
U2 - 10.1073/pnas.1112345109
DO - 10.1073/pnas.1112345109
M3 - Article
C2 - 22431635
AN - SCOPUS:84859475819
SN - 0027-8424
VL - 109
SP - 5469
EP - 5474
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 14
ER -