Do neuroinflammatory pathways contribute to serotoninergic alterations in autism? p38alpha MAPK signaling drives perturbed serotonin clearance, receptor hypersensitivity, and social behavior deficits in the SERT Ala56 mouse

Abstract

Autism Spectrum Disorder (ASD) is a prevalent neurodevelopmental disorder with no FDA approved medications that alleviate core symptoms. Aberrant proinflammatory cytokine signaling involving the interleukin-1 receptor and p38 MAPK have been reported in ASD, a disorder where 25% of subjects exhibit elevated serotonin (5-HT) blood levels (hyperserotonemia). In ASD subjects, we identified functional coding variation in the 5-HT transporter (SERT), mutations that elevate SERT activity and perturb p38 MAPK-dependent transporter regulation. Mice that express the most common of these variants, SERT Ala56, exhibit hyperserotonemia, elevated, p38 MAPK-dependent SERT phosphorylation, increased hippocampal 5-HT clearance, 5-HT receptor hypersensitivity, increased repetitive behavior and disrupted social interactions. Treatment of SERT Ala56 mice with the novel, selective, CNS penetrant, p38alpha MAPK inhibitor, MW150, or conditional elimination of p38alpha MAPK in 5-HT neurons, normalized 5-HT receptor hypersensitivity, elevated 5-HT clearance and social deficits. As p38alpha MAPK signaling supports the IL-1beta and TNF-alpha-induced activation of SERT, our findings suggest that proinflammatory, p38alpha MAPK activation may contribute to ASD risk via a perturbation of 5-HT signaling. Our studies also indicate that p38alpha MAPK may be a relevant target for the pharmacologic treatment of ASD. Funding: This 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.