Abstract
BackgroundAutism spectrum disorders (ASDs) are caused by both genetic and environmental factors. Mitochondria act to connect genes and environment by regulating gene-encoded metabolic networks according to changes in the chemistry of the cell and its environment. Mitochondrial ATP and other metabolites are mitokines—signaling molecules made in mitochondria—that undergo regulated release from cells to communicate cellular health and danger to neighboring cells via purinergic signaling. The role of purinergic signaling has not yet been explored in autism spectrum disorders.Objectives and MethodsWe used the maternal immune activation (MIA) mouse model of gestational poly(IC) exposure and treatment with the non-selective purinergic antagonist suramin to test the role of purinergic signaling in C57BL/6J mice.ResultsWe found that antipurinergic therapy (APT) corrected 16 multisystem abnormalities that defined the ASD-like phenotype in this model. These included correction of the core social deficits and sensorimotor coordination abnormalities, prevention of cerebellar Purkinje cell loss, correction of the ultrastructural synaptic dysmorphology, and correction of the hypothermia, metabolic, mitochondrial, P2Y2 and P2X7 purinergic receptor expression, and ERK1/2 and CAMKII signal transduction abnormalities.ConclusionsHyperpurinergia is a fundamental and treatable feature of the multisystem abnormalities in the poly(IC) mouse model of autism spectrum disorders. Antipurinergic therapy provides a new tool for refining current concepts of pathogenesis in autism and related spectrum disorders, and represents a fresh path forward for new drug development.
Highlights
Autism spectrum disorders (ASDs) are complex, multisystem disorders that are defined by unifying, core abnormalities in the development of language, social behavior, and repetitive behaviors
We found that antipurinergic therapy (APT) corrected 16 multisystem abnormalities that defined the ASD-like phenotype in this model
Since mitochondria are located at the hub of the wheel of metabolism and play a central role in non-infectious cellular stress [14], innate immunity [15], inflammasome activation [16], and the stereotyped antiviral response [17], we searched for a signaling system that was both traceable to mitochondria and critical for innate immunity
Summary
Autism spectrum disorders (ASDs) are complex, multisystem disorders that are defined by unifying, core abnormalities in the development of language, social behavior, and repetitive behaviors. The majority of children with ASD develop disease as the result of interactions between large sets of genes and environmental factors. We hypothesized that all of these clinical comorbidities can result from a single, evolutionarily conserved, metabolic state associated with a cellular danger response (CDR). Since mitochondria are located at the hub of the wheel of metabolism and play a central role in non-infectious cellular stress [14], innate immunity [15], inflammasome activation [16], and the stereotyped antiviral response [17], we searched for a signaling system that was both traceable to mitochondria and critical for innate immunity. Autism spectrum disorders (ASDs) are caused by both genetic and environmental factors. Mitochondrial ATP and other metabolites are mitokines—signaling molecules made in mitochondria—that undergo regulated release from cells to communicate cellular health and danger to neighboring cells via purinergic signaling. The role of purinergic signaling has not yet been explored in autism spectrum disorders
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