TY - JOUR
T1 - P38a MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse
AU - Robson, Matthew J.
AU - Quinlan, Meagan A.
AU - Margolis, Kara Gross
AU - Gajewski-Kurdziel, Paula A.
AU - Veenstra-Vander Weele, Jeremy
AU - Gershon, Michael D.
AU - Watterson, D. Martin
AU - Blakely, Randy D.
N1 - Publisher Copyright:
© 2018 National Academy of Sciences. All rights reserved.
PY - 2018/10/23
Y1 - 2018/10/23
N2 - 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.
AB - 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.
KW - Autism spectrum disorder
KW - P38 MAPK
KW - Serotonin
KW - Serotonin transporter
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U2 - 10.1073/pnas.1809137115
DO - 10.1073/pnas.1809137115
M3 - Article
C2 - 30297392
AN - SCOPUS:85055608797
SN - 0027-8424
VL - 115
SP - E10245-E10254
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 - 43
ER -