Abstract

Autism spectrum disorder (ASD) affects 2% of children, and is characterized by impaired social and communication skills together with repetitive, stereotypic behavior. The pathophysiology of ASD is complex due to genetic and environmental heterogeneity, complicating the development of therapies and making diagnosis challenging. Growing genetic evidence supports a role of disrupted Ca²⁺ signaling in ASD.

Here, we report that patient-derived fibroblasts from three monogenic models of ASD—fragile X and tuberous sclerosis TSC1 and TSC2 syndromes—display depressed Ca²⁺ release through inositol trisphosphate receptors (IP₃Rs).

This was apparent in Ca²⁺ signals evoked by G protein-coupled receptors and by photoreleased IP₃ at the levels of both global and local elementary Ca²⁺ events, suggesting fundamental defects in IP₃R channel activity in ASD. Given the ubiquitous involvement of IP₃R-mediated Ca²⁺ signaling in neuronal excitability, synaptic plasticity, gene expression and neurodevelopment, we propose dysregulated IP₃R signaling as a nexus where genes altered in ASD converge to exert their deleterious effect.

These findings highlight potential pharmaceutical targets, and identify Ca²⁺ screening in skin fibroblasts as a promising technique for early detection of individuals susceptible to ASD.