Metabolic and behavioral features of acute hyperpurinergia and the maternal immune activation mouse model of autism spectrum disorder

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.

Glial Purinergic Signaling in Neurodegeneration

“…Functionally, the P2Y1 receptor signaling pathway is one of the major purinergic signaling pathways that may contribute to altered astrocyte properties in neurodegeneration, especially in AD. P2Y1 mediates calcium waves in astrocytes, which are linked to gliotransmitter release and synchronization of astrocytic syncytium, which is critical for synaptic plasticity (149)(150)(151). Unlike in the transcriptomic studies we summarized here, previous studies showed that astrocytic P2Y1 receptor expression is elevated in AD mouse models and human AD brain, especially in close vicinity to amyloid plaques (151,152).…”

The Metallome as a Link Between the “Omes” in Autism Spectrum Disorders

“…A recent study aimed to characterize metabolomic features in hyperpurinergic conditions using a maternal immune activation mouse model. Fifty percent of plasma metabolites (202/401) from 37 pathways were altered significantly, with xanthosine, dopamine, and L-isoleucine ranked as the most altered metabolites in the maternal immune activation mice ( Zolkipli-Cunningham et al, 2021 ). A further study has focused on valproic acid-induced ASD rodent models.…”

Structural and Lipidomic Alterations of Striatal Myelin in 16p11.2 Deletion Mouse Model of Autism Spectrum Disorder

“…Our study reveals here lipidomic changes in the myelin-rich striatum in detail in the 16p11.2 ± ASD mouse model, highlighting decreased levels of key lipid components of myelin -CerG1, SM and Cer species -in 16p11.2 ± striatum (Figures 4-6). Interestingly, in the maternal immune activation (MIA) mouse model of ASD, where autism-like symptoms arise from acute hyperpurinergia, the plasma levels of 15 Cer and 15 SM species (most having a long acyl chain) have been shown to be significantly reduced (Zolkipli-Cunningham et al, 2021). Taken together, a commonality between these observations regarding ASD is altered lipid metabolism.…”