Description:

Randy D. Blakely, Ph.D.
Executive Director of FAU Brain Institute
Professor of Biomedical Science
Florida Atlantic University

Epidemiological, post-mortem and gene network analyses have pointed to changes in inflammatory signaling pathways as a contribution to risk of autism. How such changes lead to alterations in brain development and function remain ill-defined. Previously, we identified an IL-1R activated p38α MAPK signaling pathway as central to the posttranslational control of serotonin signaling via modulation of presynaptic serotonin transporter (SERT) function, consistent with recent findings of significant expression of Il-1Rs by serotonin neurons. The possibility that an IL-1R/p38α MAPK/SERT signaling pathway might have disease relevance became of interest with our identification in subjects with autism of multiple, rare, hyperfunctional SERT coding variants that display constitutive p38α MAPK-dependent activation. With a knock-in mouse expressing the most common of these variants, SERT Ala56, we demonstrated elevated CNS serotonin clearance in vivo, and demonstrate changes in CNS and GI physiology and behavior consistent with constitutive-activation of SERT function. Recently, using brain penetrant, isoform-specific, p38α MAPK inhibitors, as well as conditional, serotonin neuron-specific elimination of p38α MAPK, we have been able to normalize multiple changes in these mice. Together, our studies point to the normal use of an IL-1R/p38α MAPK signaling pathway targeting SERT in serotonin neurons to modulate behavior in response to CNS and/or peripheral innate immune system activation. Inappropriate or excessive activation of this pathway during early life may contribute to one or more facets of autism that may be manipulated through pharmacological p38α MAPK inhibition.