Work

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

Year: 2018

Type: article

Abstract: Significance Autism 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.

Source: Proceedings of the National Academy of Sciences

DOI: 10.1073/pnas.1809137115

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

Institutions: University of Cincinnati, Florida Atlantic University, Vanderbilt University, Columbia University Irving Medical Center, Columbia University, Northwestern University

Language: English

Topic: Autism Spectrum Disorder Research

Subfield: Cognitive Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Funders: Brain and Behavior Research Foundation, Pharmaceutical Research and Manufacturers of America Foundation, National Institutes of Health, National Institute on Aging, National Institute of Mental Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke

Awards: Training Program in Ion Channel and Transporter Biology, Regulation of Serotonin Transporters, Preclinical Alzheimers Disease Drug Development of Novel MAPK Inhibitors, Development of Novel p38 MAPK Inhibitors as Therapeutics for CNS Disorders, G2281486809, G3924088376, MICROENVIRONMENT IN ENTERIC NEURON DEVELOPMENT, Enduring Effects of Early-Life Serotonin Signaling, Enteric Neuronal Development as a Determinant of Intestinal Inflammation, Linkage of s100a10 (p11) to enteric 5-HT4-mediated serotonergic signaling roles in GI motility, enteric nervous system development, and co-morbid dysfunction of gut and brain, G9000136169, G9000351003

OpenAlex ID: W2897468495

FWCI: 3.076

Cites: 128

Cited by: 57

Related to: 10