Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function.
Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4-mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation.
Kara Gross
KG
Margolis
Zhishan
Z
Li
Korey
K
Stevanovic
Virginia
V
Saurman
Narek
N
Israelyan
George M
GM
Anderson
Isaac
I
Snyder
Jeremy
J
Veenstra-VanderWeele
Randy D
RD
Blakely
Michael D
MD
Gershon
D000818:Animals; D000067877:Autism Spectrum Disorder / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D017615:Enteric Nervous System / Q000002:abnormalities / Q000254:growth & development / Q000503:physiopathology; D005260:Female; D005769:Gastrointestinal Motility / Q000235:genetics / Q000502:physiology; D041981:Gastrointestinal Tract / Q000002:abnormalities* / Q000254:growth & development / Q000503:physiopathology; D014644:Genetic Variation; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D023421:Models, Animal; D055495:Neurogenesis; D011247:Pregnancy; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*
C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin