P38a MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse

Matthew J. Robson, Meagan A. Quinlan, Kara Gross Margolis, Paula A. Gajewski-Kurdziel, Jeremy Veenstra-Vander Weele, Michael D. Gershon, D. Martin Watterson, Randy D. Blakely

Research output: Contribution to journalArticlepeer-review


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 a-isoform of p38 MAPK drives SERT activation, we tested the hypothesis that CNS-penetrant, a-isoform-specific p38 MAPK inhibitors might normalize SERT Ala56 phenotypes. Strikingly, 1-week treatment of adult SERT Ala56 mice with MW150, a selective p38a MAPK inhibitor, normalized hippocampal 5-HT clearance, CNS 5-HT1A and 5-HT2A/2C receptor sensitivities, social interactions, and colonic motility. Conditional elimination of p38a 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 p38a MAPK activity as an important determinant of the physiological and behavioral perturbations of SERT Ala56 mice and, more broadly, supports consideration of p38a MAPK inhibition as a potential treatment for core and comorbid phenotypes present in ASD subjects.

Original languageEnglish (US)
Pages (from-to)E10245-E10254
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number43
StatePublished - Oct 23 2018


  • Autism spectrum disorder
  • P38 MAPK
  • Serotonin
  • Serotonin transporter

ASJC Scopus subject areas

  • General


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