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Proc Natl Acad Sci U S A. 2018 Oct 8. pii: 201809137. doi: 10.1073/pnas.1809137115. [Epub ahead of print]

p38α MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse.

Author information

1
Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL 33458.
2
Division of Pharmaceutical Sciences, University of Cincinnati, Cincinnati, OH 45220.
3
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232.
4
Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY 10032.
5
Department of Psychiatry, Columbia University College of Physicians and Surgeons/New York Psychiatric Institute, New York, NY 10032.
6
Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032.
7
Department of Pharmacology, Northwestern University School of Medicine, Chicago, IL 60611.
8
Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL 33458; rblakely@health.fau.edu.
9
Brain Institute, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL 33458.

Abstract

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.

KEYWORDS:

autism spectrum disorder; p38 MAPK; serotonin; serotonin transporter

PMID:
30297392
DOI:
10.1073/pnas.1809137115
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Conflict of interest statement

Conflict of interest statement: J.V.-V. has served on advisory boards or consulted with Roche, Novartis, and SynapDx; has research funding from Roche, Novartis, SynapDx, Seaside Therapeutics, and Forest; and has also received editorial stipends from Springer and Wiley.

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