Reduced IP3-Mediated Ca2+ Signaling in Autism Spectrum Disorders in the Context of Fragile X and Tuberous Sclerosis Syndromes

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder affecting up to 2% of children and characterized by impaired social skills, delayed or disordered language and communication skills, and repetitive, stereotypic behavior. Growing evidence supports a role of Ca2+ signaling in the pathogenesis of ASD. Inositol trisphosphate (IP3)-mediated Ca2+ release from intracellular stores participates in a variety of functions, from synaptic plasticity and memory, to long-term gene transcription changes and immune response. IP3 is produced upon stimulation of G-protein coupled receptors (GPCR) and binds to IP3 receptor/channel (IP3R) in the membrane of the endoplasmic reticulum (ER), liberating Ca2+ sequestered in the ER lumen into the cytoplasm. Here, we report that human fibroblasts from three genetically distinct monogenic models of ASD – fragile X and tuberous sclerosis TSC1 and TSC2 – uniformly display depressed Ca2+ release through IP3 receptors. We observed defects in whole-cell Ca2+ signals evoked by G-protein-coupled cell surface receptors and by photoreleased IP3, and at the level of local elementary Ca2+ events, suggesting fundamental defects in IP3R channel activity in ASD. Given its ubiquitous functions in the body, malfunctioning of IP3-mediated signaling may account for the heterogeneity of non-neuronal symptoms seen in ASD, such as gastrointestinal tract problems and immunological complications.