We are very happy to share with you that the lab has a new publication! Laura Sánchez-Benito’s PhD project has resulted in an article in which, for the first time, they identified the mechanism behind epilepsy in mitochondrial diseases, a potentially fatal symptom of this kind of disorders.
Since epileptic crises involve excessive neural activation, they worked on inhibitory neurons, known as GABAergic neurons (which release the inhibitory neurotransmitter GABA), with the hypothesis that perhaps these neurons were not functioning properly. They suspected that the problem could stem from a loss of the brain’s natural inhibitor control.
“We posed the hypothesis that mitochondrial dysfunction in the GABAergic neurons connecting two key regions of the brain, the external globus pallidus (GPe) and the subthalamic nucleus (STN), could be the reason for the hyperexcitability observed in this circuit”, explains Laura.
They used two different Leigh syndrome mice models to test the hypothesis: the KO model, in which mitochondrial function is deteriorated throughout the entire body and most of the disease’s symptoms are reproduced; and the cKO model, in which mitochondrial dysfunction only affects the GABAergic neurons of the GPe, allowing the isolation of the effects of this localized defect.
Using advanced imaging, electrophysiological and genetic techniques, they discovered that the GPe GABAergic neurons are particularly vulnerable to mitochondrial dysfunction, which led to their generalised degeneration. Also, since these neurons are in charge of keeping STN activity under control, losing them makes the nucleus become hyperactive, which produced recurrent epileptic crises in the animals.
In contrast, when the team restored the GPe mitochondrial functions, the crises almost disappeared. The mice lived longer and showed a notable improvement in neurological functions. “We were surprised to see how the loss of only one inhibitory neuron population could spread through the network and trigger epileptic crises”, Laura explains.
“Our study demonstrates that it is not the whole brain that is propelling the crisis, but rather that restoring the function of these specific neurons is enough to drastically suppress this fatal form of epilepsy”, says Albert, who coordinated the study. “Moreover, since the inactivation of STN with deep brain stimulation is already a therapy being used, this option could be considered for patients with Leigh syndrome”, he concludes.
The study, conducted in collaboration with researchers from the Institut de Neurociències d’Alacant, the Vall d’Hebron Research Institute (VHIR), and the UAB Department of Biochemistry and Molecular Biology, opens up new horizons for patients with mitochondrial diseases who currently have no therapeutic options when it comes to treating their crises.
Reference:Sánchez-Benito L, González-Torres M, Fernández-González I, Cutando L, Royo M, Compte J, Vila M, Jurado S, Sanz E, & Quintana A. (2025). Dysfunctional LHX6 pallido-subthalamic projections mediate epileptic events in a mouse model of Leigh Syndrome. J Clin Invest. DOI: 10.1172/JCI187571