IL-1beta and IL1RAPL1: Gene-environment interactions regulating synapse density and function in ASD
McAllister, A Kimberley
University of California, Davis
Weatherstone Predoctoral Fellowship
Although the incidence of autism is now 1:88, the cause of autism remains largely unknown. However, mounting evidence suggests that autism may be caused by a complex interplay between genes and the environment, and many of these factors result in changes in the synaptic connectivity of the brain. Although there is a wide range of environmental factors that have been linked to Autism Spectrum Disorder (ASD), most cause changes in the immune response. In particular, a specific signaling molecule in the immune system, called interleukin-1beta (IL-1beta), has recently been linked to ASD. Levels of IL-1beta are increased in the blood and cerebrospinal fluid of ASD patients and genetic studies show an association between mutations related to the IL-1beta signaling pathway and ASD. Based on these observations, the hypothesis is that IL-1beta is critical for gene-environment interactions that cause some forms of ASD. Because little is known about IL-1beta’s actions in the brain, the requisite first step in addressing this hypothesis is to determine if changing the levels of IL-1beta regulates the initial formation of cortical connections in the newborn brain--the phenomenon that appears to be most affected in ASD. Molecular techniques will be used to determine if disease-relevant concentrations of IL-1beta alter synapse density, identify the specific receptor that mediates these changes, and start to determine the molecular pathway that underlies these effects. Results from this project are essential for future development of in vivo rodent models to probe the causal role of IL-1beta in ASD and screen for novel therapies for this devastating disorder.