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Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model
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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334917/ https://www.ncbi.nlm.nih.gov/pubmed/25705365 http://dx.doi.org/10.1186/2040-2392-6-1 |
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author | Naviaux, Jane C Wang, Lin Li, Kefeng Bright, A Taylor Alaynick, William A Williams, Kenneth R Powell, Susan B Naviaux, Robert K |
author_facet | Naviaux, Jane C Wang, Lin Li, Kefeng Bright, A Taylor Alaynick, William A Williams, Kenneth R Powell, Susan B Naviaux, Robert K |
author_sort | Naviaux, Jane C |
collection | PubMed |
description | 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2040-2392-6-1) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4334917 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-43349172015-02-21 Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model Naviaux, Jane C Wang, Lin Li, Kefeng Bright, A Taylor Alaynick, William A Williams, Kenneth R Powell, Susan B Naviaux, Robert K Mol Autism Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2040-2392-6-1) contains supplementary material, which is available to authorized users. BioMed Central 2015-01-13 /pmc/articles/PMC4334917/ /pubmed/25705365 http://dx.doi.org/10.1186/2040-2392-6-1 Text en © Naviaux et al.; licensee BioMed Central. 2015 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Naviaux, Jane C Wang, Lin Li, Kefeng Bright, A Taylor Alaynick, William A Williams, Kenneth R Powell, Susan B Naviaux, Robert K Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model |
title | Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model |
title_full | Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model |
title_fullStr | Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model |
title_full_unstemmed | Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model |
title_short | Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model |
title_sort | antipurinergic therapy corrects the autism-like features in the fragile x (fmr1 knockout) mouse model |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334917/ https://www.ncbi.nlm.nih.gov/pubmed/25705365 http://dx.doi.org/10.1186/2040-2392-6-1 |
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