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

Abstract

SignificanceAutism 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.

Functions of p38 MAP Kinases in the Central Nervous System

“…5HT cells in the dorsal raphe nucleus respond to exposure of rodents to stress with activation of κ-opioid receptors and p38α (Lemos et al, 2012). Consistently, 5HT neuron specific deletion of p38α or administration of p38α inhibitor (MW150) restores phenotypes of a SERT mutant mouse model of social defeat stress (Robson et al, 2018), and pan-neuronal deletion of p38α resulted in reduced resilience to novelty stress and an altered anxiety response (Stefanoska et al, 2018). Pan-neuronal p38α-deficient mice had increased activity of JNK in the forebrain and stress response in these mice was restored by inhibition of JNK (Stefanoska et al, 2018).…”

Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy

“…We treated SMA mice daily by intraperitoneal (i.p.) injection with either saline or 5 mg/kg of MW150-a dose previously demonstrated to effectively inhibit p38a MAPK in the CNS and to improve the phenotype of mouse models of neurological disease (Robson et al, 2018;Roy et al, 2015Roy et al, , 2019Rutigliano et al, 2018;Zhou et al, 2017). Importantly, MW150 treatment robustly decreased the levels of p53 S18 phosphorylation but not the induction of p53 in vulnerable L5 MMC SMA motor neurons relative to vehicle-treated SMA mice at P11 ( Figures 5E-5H), directly linking p38a MAPK activation to the phosphorylation of p53 S18 in SMA motor neurons.…”

The synthetic cathinone psychostimulant α‐PPP antagonizes serotonin 5‐HT2A receptors: In vitro and in vivo evidence

“…MDPPP also has higher affinity and inhibitory potency at SERT, relative to α‐PPP . Alterations in SERT activity can affect the DOI HTR . For example, blocking SERT increases synaptic 5‐HT levels which could compete with DOI for 5‐HT 2A binding sites, decreasing its effects.…”

“…47,48 Alterations in SERT activity can affect the DOI HTR. 49 For example, blocking SERT increases synaptic 5-HT levels which could compete with DOI for 5-HT 2A binding sites, decreasing its effects. Pre-treatment with 3 or 10 mg/kg MDPPP (N = 7 each), however, had no significant effect on the HTR elicited by DOI (P = 0.92 and 0.19, respectively, compared to vehicle/DOI).…”