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An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes
Autism spectrum disorders (ASDs) are characterized by a deficit in social communication, pathologic repetitive behaviors, restricted interests, and electroencephalogram (EEG) aberrations. While exhaustive analysis of nuclear DNA (nDNA) variation has revealed hundreds of copy number variants (CNVs) a...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017921/ https://www.ncbi.nlm.nih.gov/pubmed/33536343 http://dx.doi.org/10.1073/pnas.2021429118 |
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author | Yardeni, Tal Cristancho, Ana G. McCoy, Almedia J. Schaefer, Patrick M. McManus, Meagan J. Marsh, Eric D. Wallace, Douglas C. |
author_facet | Yardeni, Tal Cristancho, Ana G. McCoy, Almedia J. Schaefer, Patrick M. McManus, Meagan J. Marsh, Eric D. Wallace, Douglas C. |
author_sort | Yardeni, Tal |
collection | PubMed |
description | Autism spectrum disorders (ASDs) are characterized by a deficit in social communication, pathologic repetitive behaviors, restricted interests, and electroencephalogram (EEG) aberrations. While exhaustive analysis of nuclear DNA (nDNA) variation has revealed hundreds of copy number variants (CNVs) and loss-of-function (LOF) mutations, no unifying hypothesis as to the pathophysiology of ASD has yet emerged. Based on biochemical and physiological analyses, it has been hypothesized that ASD may be the result of a systemic mitochondrial deficiency with brain-specific manifestations. This proposal has been supported by recent mitochondrial DNA (mtDNA) analyses identifying both germline and somatic mtDNA variants in ASD. If mitochondrial defects do predispose to ASD, then mice with certain mtDNA mutations should present with autism endophenotypes. To test this prediction, we examined a mouse strain harboring an mtDNA ND6 gene missense mutation (P25L). This mouse manifests impaired social interactions, increased repetitive behaviors and anxiety, EEG alterations, and a decreased seizure threshold, in the absence of reduced hippocampal interneuron numbers. EEG aberrations were most pronounced in the cortex followed by the hippocampus. Aberrations in mitochondrial respiratory function and reactive oxygen species (ROS) levels were also most pronounced in the cortex followed by the hippocampus, but absent in the olfactory bulb. These data demonstrate that mild systemic mitochondrial defects can result in ASD without apparent neuroanatomical defects and that systemic mitochondrial mutations can cause tissue-specific brain defects accompanied by regional neurophysiological alterations. |
format | Online Article Text |
id | pubmed-8017921 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-80179212021-04-12 An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes Yardeni, Tal Cristancho, Ana G. McCoy, Almedia J. Schaefer, Patrick M. McManus, Meagan J. Marsh, Eric D. Wallace, Douglas C. Proc Natl Acad Sci U S A Biological Sciences Autism spectrum disorders (ASDs) are characterized by a deficit in social communication, pathologic repetitive behaviors, restricted interests, and electroencephalogram (EEG) aberrations. While exhaustive analysis of nuclear DNA (nDNA) variation has revealed hundreds of copy number variants (CNVs) and loss-of-function (LOF) mutations, no unifying hypothesis as to the pathophysiology of ASD has yet emerged. Based on biochemical and physiological analyses, it has been hypothesized that ASD may be the result of a systemic mitochondrial deficiency with brain-specific manifestations. This proposal has been supported by recent mitochondrial DNA (mtDNA) analyses identifying both germline and somatic mtDNA variants in ASD. If mitochondrial defects do predispose to ASD, then mice with certain mtDNA mutations should present with autism endophenotypes. To test this prediction, we examined a mouse strain harboring an mtDNA ND6 gene missense mutation (P25L). This mouse manifests impaired social interactions, increased repetitive behaviors and anxiety, EEG alterations, and a decreased seizure threshold, in the absence of reduced hippocampal interneuron numbers. EEG aberrations were most pronounced in the cortex followed by the hippocampus. Aberrations in mitochondrial respiratory function and reactive oxygen species (ROS) levels were also most pronounced in the cortex followed by the hippocampus, but absent in the olfactory bulb. These data demonstrate that mild systemic mitochondrial defects can result in ASD without apparent neuroanatomical defects and that systemic mitochondrial mutations can cause tissue-specific brain defects accompanied by regional neurophysiological alterations. National Academy of Sciences 2021-02-09 2021-02-03 /pmc/articles/PMC8017921/ /pubmed/33536343 http://dx.doi.org/10.1073/pnas.2021429118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Yardeni, Tal Cristancho, Ana G. McCoy, Almedia J. Schaefer, Patrick M. McManus, Meagan J. Marsh, Eric D. Wallace, Douglas C. An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes |
title | An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes |
title_full | An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes |
title_fullStr | An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes |
title_full_unstemmed | An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes |
title_short | An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes |
title_sort | mtdna mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017921/ https://www.ncbi.nlm.nih.gov/pubmed/33536343 http://dx.doi.org/10.1073/pnas.2021429118 |
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