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ResearchIn-Press PreviewInflammationNeuroscience Open Access | 10.1172/JCI187571

Dysfunctional LHX6 pallido-subthalamic projections mediate epileptic events in a mouse model of Leigh Syndrome

Laura Sánchez-Benito,1 Melania González-Torres,1 Irene Fernández-González,1 Laura Cutando,1 María Royo,2 Joan Compte,3 Miquel Vila,1 Sandra Jurado,2 Elisenda Sanz,1 and Albert Quintana1

1Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain

2Institute of Neuroscience, CSIC-UMH, Alicante, Spain

3Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain

Find articles by Sánchez-Benito, L. in: PubMed | Google Scholar

1Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain

2Institute of Neuroscience, CSIC-UMH, Alicante, Spain

3Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain

Find articles by González-Torres, M. in: PubMed | Google Scholar

1Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain

2Institute of Neuroscience, CSIC-UMH, Alicante, Spain

3Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain

Find articles by Fernández-González, I. in: PubMed | Google Scholar

1Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain

2Institute of Neuroscience, CSIC-UMH, Alicante, Spain

3Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain

Find articles by Cutando, L. in: PubMed | Google Scholar

1Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain

2Institute of Neuroscience, CSIC-UMH, Alicante, Spain

3Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain

Find articles by Royo, M. in: PubMed | Google Scholar

1Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain

2Institute of Neuroscience, CSIC-UMH, Alicante, Spain

3Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain

Find articles by Compte, J. in: PubMed | Google Scholar |

1Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain

2Institute of Neuroscience, CSIC-UMH, Alicante, Spain

3Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain

Find articles by Vila, M. in: PubMed | Google Scholar

1Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain

2Institute of Neuroscience, CSIC-UMH, Alicante, Spain

3Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain

Find articles by Jurado, S. in: PubMed | Google Scholar

1Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain

2Institute of Neuroscience, CSIC-UMH, Alicante, Spain

3Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain

Find articles by Sanz, E. in: PubMed | Google Scholar

1Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain

2Institute of Neuroscience, CSIC-UMH, Alicante, Spain

3Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain

Find articles by Quintana, A. in: PubMed | Google Scholar |

Published October 2, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI187571.
Copyright © 2025, Sánchez-Benito et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 2, 2025 - Version history
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Abstract

Deficits in the mitochondrial energy-generating machinery cause mitochondrial disease (MD), a group of untreatable and usually fatal disorders. Among many severe symptoms, refractory epileptic events are a common neurological presentation of MD. However, the neuronal substrates and circuits for MD-induced epilepsy remain unclear. Here, using mouse models of Leigh Syndrome, a severe form of MD associated to epilepsy, that lack mitochondrial complex I subunit NDUFS4 in a constitutive or conditional manner, we demonstrate that mitochondrial dysfunction leads to a reduction in the number of GABAergic neurons in the rostral external globus pallidus (GPe), and identify a specific affectation of pallidal Lhx6-expressing inhibitory neurons, contributing to altered GPe excitability. Our findings further reveal that viral vector-mediated Ndufs4 re-expression in the GPe effectively prevents seizures and improves the survival in the models. Additionally, we highlight the subthalamic nucleus (STN) as a critical structure in the neural circuit involved in mitochondrial epilepsy, as its inhibition effectively reduces epileptic events. Thus, we have identified a role for pallido-subthalamic projections in the development of epilepsy in the context of mitochondrial dysfunction. Our results suggest STN inhibition as a potential therapeutic intervention for refractory epilepsy in patients with MD providing promising leads in the quest to identify effective treatments.

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