Abstract
Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders without any defined uniting pathophysiology. Ca2+ signaling is emerging as a potential node in the genetic architecture of the disorder. We previously reported decreased inositol trisphosphate (IP3)-mediated Ca2+ release from the endoplasmic reticulum in several rare monogenic syndromes highly comorbid with autism – fragile X and tuberous sclerosis types 1 and 2 syndromes. We now extend those findings to a cohort of subjects with sporadic ASD without any known mutations. We developed and applied a high throughput Fluorometric Imaging Plate Reader (FLIPR) assay to monitor agonist-evoked Ca2+ signals in human primary skin fibroblasts. Our results indicate that IP3 -mediated Ca2+ release from the endoplasmic reticulum in response to activation of purinergic receptors is significantly depressed in subjects with sporadic as well as rare syndromic forms of ASD. We propose that deficits in IP3-mediated Ca2+ signaling represent a convergent hub function shared across the spectrum of autistic disorders – whether caused by rare highly penetrant mutations or sporadic forms – and holds promise as a biomarker for diagnosis and novel drug discovery.
Highlights
Light of the growing genetic evidence supporting its role in susceptibility to ASD21,23–25, and its ubiquitous participation in cellular functions as diverse as neuronal excitability[26,27], neurotransmitter release[28,29], cell secretion[30,31], gene expression, and apoptosis[32,33]
We proposed that multiple genetic lesions leading to Autism Spectrum Disorder (ASD) converge to perturb normal Ca2+ signaling, and that depressed function of the IP3 receptor/channels (IP3Rs) Ca2+ release channels in the endoplasmic reticulum (ER) play a key ‘hub’ role in the pathogenesis of ASD – one that might serve as a diagnostic biomarker and potential target for novel drug discovery[24,34,37]
We had previously demonstrated that patient-derived fibroblasts from three monogenic models of ASD (FSX, TSC1 and TSC2) display depressed Ca2+ release evoked by purinergic receptor activation of IP3 signaling, and proposed that dysregulation of IP3 signaling constitutes a nexus where genes altered in ASD converge to exert their deleterious effect[34]
Summary
Light of the growing genetic evidence supporting its role in susceptibility to ASD21,23–25, and its ubiquitous participation in cellular functions as diverse as neuronal excitability[26,27], neurotransmitter release[28,29], cell secretion[30,31], gene expression, and apoptosis[32,33]. Responses in fibroblasts obtained from subjects exhibiting each of these monogenic syndromes were depressed as compared with matched controls. These deficits could not be attributed to underfilling of ER Ca2+ stores, or to diminished expression of IP3R proteins. We proposed that multiple genetic lesions leading to ASD converge to perturb normal Ca2+ signaling, and that depressed function of the IP3R Ca2+ release channels in the ER play a key ‘hub’ role in the pathogenesis of ASD – one that might serve as a diagnostic biomarker and potential target for novel drug discovery[24,34,37]. We observe that ATP-evoked Ca2+ release is depressed in fibroblasts from a majority of sporadic ASD subjects, to an extent similar to that seen in cells from subjects with monogenic forms of ASD
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