Abstract
BackgroundThis study was designed to test a new approach to drug treatment of autism spectrum disorders (ASDs) in the Fragile X (Fmr1) knockout mouse model.MethodsWe used behavioral analysis, mass spectrometry, metabolomics, electron microscopy, and western analysis to test the hypothesis that the disturbances in social behavior, novelty preference, metabolism, and synapse structure are treatable with antipurinergic therapy (APT).ResultsWeekly treatment with the purinergic antagonist suramin (20 mg/kg intraperitoneally), started at 9 weeks of age, restored normal social behavior, and improved metabolism, and brain synaptosomal structure. Abnormalities in synaptosomal glutamate, endocannabinoid, purinergic, and IP3 receptor expression, complement C1q, TDP43, and amyloid β precursor protein (APP) were corrected. Comprehensive metabolomic analysis identified 20 biochemical pathways associated with symptom improvements. Seventeen pathways were shared with human ASD, and 11 were shared with the maternal immune activation (MIA) model of ASD. These metabolic pathways were previously identified as functionally related mediators of the evolutionarily conserved cell danger response (CDR).ConclusionsThe data show that antipurinergic therapy improves the multisystem, ASD-like features of both the environmental MIA, and the genetic Fragile X models. These abnormalities appeared to be traceable to mitochondria and regulated by purinergic signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/2040-2392-6-1) contains supplementary material, which is available to authorized users.
Highlights
This study was designed to test a new approach to drug treatment of autism spectrum disorders (ASDs) in the Fragile X (Fmr1) knockout mouse model
Confirmation of Fragile X protein knockout We confirmed the absence of Fragile X protein (FMRP) expression in Fragile X mental retardation gene locus 1 (Fmr1) knockout mice, and its presence in FVB and C57BL/6J controls by western blot analysis before phenotyping the Fmr1 knockout animals used in this study (Additional file 1: Figure S1)
We found that Fmr1 null males showed a 26% reduction in social preference, as measured by the time spent interacting with a stranger mouse compared to an inanimate object
Summary
This study was designed to test a new approach to drug treatment of autism spectrum disorders (ASDs) in the Fragile X (Fmr1) knockout mouse model. In our previous work we found that disturbances in purine metabolism and purinergic signaling were robust features and effective targets for treatment in the environmental MIA mouse model of autism [8,9]. The first genetic causes of autism identified were traced to abnormalities in purine and pyrimidine metabolism [14,15]. These observations led us to test the role of purinergic signaling in a genetic mouse model of ASD. We selected the Fragile X model to test the hypothesis that abnormalities in purinergic signaling might underlie both the environmental MIA and genetic Fragile X models
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