Abstract
Since 2012, studies in mice, rats, and humans have suggested that abnormalities in purinergic signaling may be a final common pathway for many genetic and environmental causes of autism spectrum disorder (ASD). The current study in mice was conducted to characterize the bioenergetic, metabolomic, breathomic, and behavioral features of acute hyperpurinergia triggered by systemic injection of the purinergic agonist and danger signal, extracellular ATP (eATP). Responses were studied in C57BL/6J mice in the maternal immune activation (MIA) model and controls. Basal metabolic rates and locomotor activity were measured in CLAMS cages. Plasma metabolomics measured 401 metabolites. Breathomics measured 98 volatile organic compounds. Intraperitoneal eATP dropped basal metabolic rate measured by whole body oxygen consumption by 74% ± 6% (mean ± SEM) and rectal temperature by 6.2˚ ± 0.3˚C in 30 minutes. Over 200 metabolites from 37 different biochemical pathways where changed. Breathomics showed an increase in exhaled carbon monoxide, dimethylsulfide, and isoprene. Metabolomics revealed an acute increase in lactate, citrate, purines, urea, dopamine, eicosanoids, microbiome metabolites, oxidized glutathione, thiamine, niacinamide, and pyridoxic acid, and decreased folate-methylation-1-carbon intermediates, amino acids, short and medium chain acyl-carnitines, phospholipids, ceramides, sphingomyelins, cholesterol, bile acids, and vitamin D similar to some children with ASD. MIA animals were hypersensitive to postnatal exposure to eATP or poly(IC), which produced a rebound increase in body temperature that lasted several weeks before returning to baseline. Acute hyperpurinergia produced metabolic and behavioral changes in mice. The behaviors and metabolic changes produced by ATP injection were associated with mitochondrial functional changes that were profound but reversible.
Highlights
Over the past decade our group has tested a new unifying hypothesis for the origin and treatment of autism spectrum disorder (ASD) in both environmental and genetic animal models [1,2,3] and a small human clinical trial [4]
The extracellular Adenosine triphosphate (ATP) serves as a pro-inflammatory signal and damage associated molecular pattern (DAMP) [15, 16] that is an effector of the cell danger response (CDR) [17]
ATP injection produced dramatic changes in behavior that were similar to anxiety-associated behaviors that have been studied in many species and associated with alarm signaling [88, 91]
Summary
Over the past decade our group has tested a new unifying hypothesis for the origin and treatment of autism spectrum disorder (ASD) in both environmental and genetic animal models [1,2,3] and a small human clinical trial [4] This unifying hypothesis proposes that the behavioral symptoms and neurobiology of ASD are the result of a metabolic syndrome that arises from abnormalities in purinergic signaling. Negative threats refer to the absence of or deficiencies in needed resources like oxygen, water, calories, vitamins, nutrients, social interaction [13], or even gravity [14]. Each of these stresses produces functional changes in mitochondria and leads to an increase in cellular ATP release. The leakage of ATP to the extracellular space has the effect of decreasing intracellular ATP pools and energy reserves, prompting further adaptive changes in mitochondria, metabolism, and gene expression
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