APA
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Robson, M., Quinlan, M., Margolis, K., Gajewski-Kurdziel, P. A., Veenstra-VanderWeele, J., Gershon, M., … Blakely, R. (2018). p38α MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse. Proceedings of the National Academy of Sciences of the United States of America.
Chicago/Turabian
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Robson, M., M. Quinlan, K. Margolis, Paula A. Gajewski-Kurdziel, J. Veenstra-VanderWeele, M. Gershon, D. Watterson, and R. Blakely. “p38α MAPK Signaling Drives Pharmacologically Reversible Brain and Gastrointestinal Phenotypes in the SERT Ala56 Mouse.” Proceedings of the National Academy of Sciences of the United States of America (2018).
MLA
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Robson, M., et al. “p38α MAPK Signaling Drives Pharmacologically Reversible Brain and Gastrointestinal Phenotypes in the SERT Ala56 Mouse.” Proceedings of the National Academy of Sciences of the United States of America, 2018.
BibTeX Click to copy
@article{m2018a,
title = {p38α MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse},
year = {2018},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
author = {Robson, M. and Quinlan, M. and Margolis, K. and Gajewski-Kurdziel, Paula A. and Veenstra-VanderWeele, J. and Gershon, M. and Watterson, D. and Blakely, R.}
}
Significance Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by communication and social behavior deficits, repetitive behaviors, and medical comorbidities, including gastrointestinal dysfunction. No pharmacologic treatments are available that ameliorate core symptoms. Genetic variants in the serotonin transporter (SERT) are linked to ASD. Here we demonstrate that administration of a CNS-penetrant p38α MAPK antagonist normalizes multiple physiological and behavioral perturbations reminiscent of ASD in adult, SERT Ala56 mice. Conditional genetic manipulations validate a requirement for 5-HT neuron p38α MAPK signaling in establishing perturbations observed in SERT Ala56 mice. Our findings suggest that p38α MAPK may be a potential target for treatment of adults with ASD, particularly in relation to traits driven by elevated SERT activity and diminished 5-HT signaling. Autism spectrum disorder (ASD) is a common neurobehavioral disorder with limited treatment options. Activation of p38 MAPK signaling networks has been identified in ASD, and p38 MAPK signaling elevates serotonin (5-HT) transporter (SERT) activity, effects mimicked by multiple, hyperfunctional SERT coding variants identified in ASD subjects. Mice expressing the most common of these variants (SERT Ala56) exhibit hyperserotonemia, a biomarker observed in ASD subjects, as well as p38 MAPK-dependent SERT hyperphosphorylation, elevated hippocampal 5-HT clearance, hypersensitivity of CNS 5-HT1A and 5-HT2A/2C receptors, and behavioral and gastrointestinal perturbations reminiscent of ASD. As the α-isoform of p38 MAPK drives SERT activation, we tested the hypothesis that CNS-penetrant, α-isoform–specific p38 MAPK inhibitors might normalize SERT Ala56 phenotypes. Strikingly, 1-week treatment of adult SERT Ala56 mice with MW150, a selective p38α MAPK inhibitor, normalized hippocampal 5-HT clearance, CNS 5-HT1A and 5-HT2A/2C receptor sensitivities, social interactions, and colonic motility. Conditional elimination of p38α MAPK in 5-HT neurons of SERT Ala56 mice restored 5-HT1A and 5-HT2A/2C receptor sensitivities as well as social interactions, mirroring effects of MW150. Our findings support ongoing p38α MAPK activity as an important determinant of the physiological and behavioral perturbations of SERT Ala56 mice and, more broadly, supports consideration of p38α MAPK inhibition as a potential treatment for core and comorbid phenotypes present in ASD subjects.
