Dysfunctional LHX6 pallido-subthalamic projections mediate epileptic events in a mouse model of Leigh syndrome
Year: 2025
Type: article
Abstract: Deficits in the mitochondrial energy-generating machinery cause mitochondrial disease, a group of untreatable and usually fatal disorders. Refractory epileptic events are a common neurological presentation of mitochondrial disease, including Leigh syndrome, a severe form of mitochondrial disease associated with epilepsy. However, the neuronal substrates and circuits for mitochondrial disease-induced epilepsy remain unclear. Here, using mouse models of Leigh syndrome that lack mitochondrial complex I subunit NDUFS4 in a constitutive or conditional manner, we demonstrated that mitochondrial dysfunction leads to a reduction of GABAergic neurons in the rostral external globus pallidus (GPe) and identified a specific affectation of pallidal Lhx6-expressing inhibitory neurons contributing to altered GPe excitability. Our findings revealed that viral vector-mediated Ndufs4 reexpression in the GPe effectively prevented seizures and improved 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 epilepsy development in the context of mitochondrial dysfunction. Our results suggest STN inhibition as a potential therapeutic intervention for refractory epilepsy in patients with mitochondrial disease, providing promising leads in the quest to identify effective treatments.
DOI: 10.1172/jci187571
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: Fundació la Marató de TV3, “la Caixa” Foundation, Ministerio de Ciencia, Innovación y Universidades, Ministerio de Economía y Competitividad, Institució Catalana de Recerca i Estudis Avançats, Ministerio de Ciencia e Innovación, Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona, Agència de Gestió d'Ajuts Universitaris i de Recerca, Agencia Estatal de Investigación, H2020 European Research Council
Awards: G1021124147, G1593505902, G1790346726, Elucidating Neuronal Susceptibility to Mitochondrial Disease, G1855990336, G2072008565, G2262748287, G2290189609, G2663791776, G3022770426, G3480869486, G3515503884, G3685821485, G3690828678, G3874902637, G4184856506, G425668148, G4675981416, G4839286238, G4944594896, G5132640529, G5177909507, G5421974903, G5446173826, G5511447562, G5554424168, G5743783909, G5805502524, G5852091828, G591310736, G6000299404, G6518943365, G661728406, G7003836975, G7685134749, G8434830731, G8525082811, G8682265371, G8684520763, G884281791, G8920660035
OpenAlex ID: W4414758214