Calcium Signaling in Autism
This project is testing the hypothesis that CGG trinucleotide repeats in theFMR1 gene influence susceptibility to developmental neurotoxicants during gestation. We have produced iPSC-derived neuronal precursor cells (NPCs) from isolated fibroblast clones and have differentiated them into neurons possessing either a normal FMR1 allele active (neurotypical neurons) or an active FMR1 CGG repeat expansion in the mid-premutation range that display morphological and signaling defects relevant to autism. A major advantage of these neurotypical and susceptible neuronal cell models is that they originate from the same individual; thus, individual genetic background variation is excluded as a confounding variable. Such isogenic isoautosomal neuronal models will permit for the first time investigations of how a defined autism susceptibility gene influences susceptibility to environmental factors, specifically neurotoxicants and cytokine/chemokine profiles identified in the gestational environment of mothers at high risk for giving birth to an autistic child. Our approach also permits detailed analysis of the molecular and cellular mechanisms by which gene-environment interactions promote neurodevelopmental impairments relevant to autism.