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Mol Autism. 2015 Jan 13;6:1. doi: 10.1186/2040-2392-6-1. eCollection 2015.

Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model.

Author information

1
Department of Psychiatry, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C102, San Diego, CA 92103-8467 USA.
2
The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C102, San Diego, CA 92103-8467 USA ; Department of Medicine, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C102, San Diego, CA 92103-8467 USA.
3
The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C102, San Diego, CA 92103-8467 USA ; Department of Medicine, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C102, San Diego, CA 92103-8467 USA ; General Atomics, Inc, San Diego, CA USA.
4
Department of Psychiatry, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C102, San Diego, CA 92103-8467 USA ; Research Service, VA San Diego Healthcare System, La Jolla, CA USA.
5
The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C102, San Diego, CA 92103-8467 USA ; Department of Medicine, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C102, San Diego, CA 92103-8467 USA ; Department of Pediatrics, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C102, San Diego, CA 92103-8467 USA ; Department of Pathology, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C102, San Diego, CA 92103-8467 USA ; Veterans Affairs Center for Excellence in Stress and Mental Health (CESAMH), La Jolla, CA USA.

Abstract

BACKGROUND:

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.

METHODS:

We 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).

RESULTS:

Weekly 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).

CONCLUSIONS:

The 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.

KEYWORDS:

Antipurinergic therapy (APT); Autism spectrum disorders; Cell danger response (CDR); Environment; Fragile X syndrome; Genetics; Maternal immune activation (MIA); Metabolism; Metabolomics; Mitochondria; Purinergic signaling

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