Chronic Antagonism of p38α MAPK Normalizes Serotonin Clearance, Serotonin Receptor Hypersensitivity and Social Behavior Deficits in a Genetic Murine Model of Autism Spectrum Disorder
Authors: Robson Matthew James , Quinlan Meagan A. , Veenstra‐VanderWeele Jeremy , Watterson D. Martin , Blakely Randy D. 
Published: November 2023

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder exhibiting language and communication deficits, perturbations in social interactions, and repetitive behaviors. The estimated annual economic costs of ASD within the United States alone is over $100 billion. Compounding this problem, no FDA approved medications are currently available that mitigate the core symptoms of the disorder. Genetic variation in the SLC6A4 gene encoding the serotonin (5‐HT) transporter (SERT) has been linked to ASD and hyperserotonemia, or elevated blood 5‐HT levels, is a well‐replicated ASD biomarker. Transgenic mice expressing the ASD‐associated SERT coding variant Ala56 exhibit hyperserotonemia, elevated in vivo 5‐HT clearance, a hypersensitivity of 5‐HT1A and 5‐HT2A receptors and multiple ASD‐like behavioral phenotypes including repetitive behaviors and deficits in social interactions. Additionally, expression of SERT Ala56 results in the p38 MAPK‐dependent hyperphosphorylation of SERT, a state previously linked to enhanced activity of the transporter. There are four known isoforms of p38 MAPK denoted α, β, γ, and δ. Previous genetic and molecular studies have revealed that p38α MAPK is the primary isoform responsible for SERT regulation. We hypothesized that selective, CNS penetrant p38α MAPK inhibitors such as the recently developed MW108 or MW150 might attenuate one or more ASD‐like phenotypes in the SERT Ala56 model. Chronic treatment with MW150 (5 mg/kg, QD × 1 week) was found to normalize SERT Ala56‐mediated increases in hippocampal 5‐HT clearance and in vivo hypersensitivity of 5‐HT1A and 5‐HT2A receptors. Furthermore, chronic MW150 treatment normalized SERT Ala56‐mediated ASD‐like social deficits in the tube test. These effects arose without concomitant changes in midbrain SERT protein levels or changes in tissue levels of monoamine neurotransmitters or their metabolites. As a single acute MW150 treatment was without effect on receptor and behavioral indices, we hypothesize that changes in SERT activity downstream of p38α MAPK inhibition induce time‐dependent plasticities that ultimately normalize 5‐HT signaling potential and behavior. The efficacy of these treatments in adult animals points to an ongoing impact of p38α MAPK in driving enhanced SERT activity, altered 5‐HT signaling and specific ASD‐like behavioral perturbations evident in the SERT Ala56 model. These are the first studies to document the pharmacologic reversal of ASD‐like phenotypes via the selective inhibition of p38α MAPK signaling. Our studies support the further evaluation of p38α MAPK‐based treatments as potential pharmacotherapies for ASD.Support or Funding InformationThis work was supported by NIH grants MH078028, MH094527, NS007491 and U01AG043415. Additional support was provided by the Simons Foundation Autism Research Initiative and the PhRMA Foundation.