Defined neuronal populations drive fatal phenotype in a mouse model of Leigh Syndrome
Abstract
Mitochondrial deficits in energy production cause untreatable and fatal pathologies known as mitochondrial disease (MD). Central nervous system affectation is critical in Leigh Syndrome (LS), a common MD presentation, leading to motor and respiratory deficits, seizures and premature death. However, only specific neuronal populations are affected. Furthermore, their molecular identity and their contribution to the disease remains unknown. Here, using a mouse model of LS lacking the mitochondrial complex I subunit Ndufs4, we dissect the critical role of genetically-defined neuronal populations in LS progression. Ndufs4 inactivation in Vglut2-expressing glutamatergic neurons leads to decreased neuronal firing, brainstem inflammation, motor and respiratory deficits, and early death. In contrast, Ndufs4 deletion in GABAergic neurons causes basal ganglia inflammation without motor or respiratory involvement, but accompanied by hypothermia and severe epileptic seizures preceding death. These results provide novel insight in the cell type-specific contribution to the pathology, dissecting the underlying cellular mechanisms of MD.
Data availability
Normalized and raw data have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (accession number GSE125470).
-
Gene expression analysis in the Brainstem of Vglut2:Ndufs4cKO miceNCBI Gene Expression Omnibus, GSE125470.
Article and author information
Author details
Funding
Ministerio de Economía y Competitividad (JCI-2015-24576)
- Irene Bolea
Ministerio de Economía y Competitividad (SAF2017-88108-R)
- Albert Quintana
Agència de Gestió d'Ajuts Universitaris i de Recerca (2017SGR- 323)
- Albert Quintana
CIBERNED (CB06/05/1105)
- Xavier Navarro
TERCEL (RD16/0011/0014)
- Xavier Navarro
Instituto de Salud Carlos III
- Xavier Navarro
European Regional Development Funds
- Xavier Navarro
Ministerio de ciencia, investigación y universidades (RTI2018-101838-J-I00)
- Elisenda Sanz
European Commission (H2020-MSCA-COFUND-2014-665919)
- Alejandro Gella
European Commission (H2020-MSCA-IF-2014-658352)
- Elisenda Sanz
Ministerio de Economía y Competitividad (BES-2015-073041)
- Patricia Prada-Dacasa
Seattle Children's Research Institute (Seed Funds)
- Albert Quintana
Northwest Mitochondrial Guild (Seed Funds)
- Albert Quintana
Ministerio de Economía y Competitividad (RyC-2012-1187)
- Albert Quintana
European Research Council (ERC-2014-StG-638106)
- Albert Quintana
Ministerio de Economía y Competitividad (SAF2014-57981P)
- Albert Quintana
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Matt Kaeberlein, University of Washington, United States
Ethics
Animal experimentation: All experiments were conducted following the recommendations in the Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee of the Seattle Children´s Research Institute (#00108) and Universitat Autònoma de Barcelona (CEEAH 2925, 3295, 4114, 4155). All surgeries were performed under anesthesia, and every effor was made to minimize suffering.
Version history
- Received: March 26, 2019
- Accepted: August 11, 2019
- Accepted Manuscript published: August 12, 2019 (version 1)
- Version of Record published: September 6, 2019 (version 2)
Copyright
© 2019, Bolea et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 4,032
- Page views
-
- 532
- Downloads
-
- 27
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
Cortical folding is an important feature of primate brains that plays a crucial role in various cognitive and behavioral processes. Extensive research has revealed both similarities and differences in folding morphology and brain function among primates including macaque and human. The folding morphology is the basis of brain function, making cross-species studies on folding morphology important for understanding brain function and species evolution. However, prior studies on cross-species folding morphology mainly focused on partial regions of the cortex instead of the entire brain. Previously, our research defined a whole-brain landmark based on folding morphology: the gyral peak. It was found to exist stably across individuals and ages in both human and macaque brains. Shared and unique gyral peaks in human and macaque are identified in this study, and their similarities and differences in spatial distribution, anatomical morphology, and functional connectivity were also dicussed.
-
- Neuroscience
Complex skills like speech and dance are composed of ordered sequences of simpler elements, but the neuronal basis for the syntactic ordering of actions is poorly understood. Birdsong is a learned vocal behavior composed of syntactically ordered syllables, controlled in part by the songbird premotor nucleus HVC (proper name). Here, we test whether one of HVC’s recurrent inputs, mMAN (medial magnocellular nucleus of the anterior nidopallium), contributes to sequencing in adult male Bengalese finches (Lonchura striata domestica). Bengalese finch song includes several patterns: (1) chunks, comprising stereotyped syllable sequences; (2) branch points, where a given syllable can be followed probabilistically by multiple syllables; and (3) repeat phrases, where individual syllables are repeated variable numbers of times. We found that following bilateral lesions of mMAN, acoustic structure of syllables remained largely intact, but sequencing became more variable, as evidenced by ‘breaks’ in previously stereotyped chunks, increased uncertainty at branch points, and increased variability in repeat numbers. Our results show that mMAN contributes to the variable sequencing of vocal elements in Bengalese finch song and demonstrate the influence of recurrent projections to HVC. Furthermore, they highlight the utility of species with complex syntax in investigating neuronal control of ordered sequences.