A team led by the UAB Institut de Neurociències (INc-UAB) has for the first time identified the mechanism behind a potentially fatal type of epilepsy, a symptom of mitochondrial diseases. The discovery, based on mouse models, challenges the traditional idea that these disorders are caused by a generalised energy deficiency and instead reveals a precise disfunction in specific brain circuits.
Mitochondrial diseases are a group of very severe disorders caused by defects in the mitochondria, the machinery in charge of producing cell energy. They affect approximately one out of every 4,300 births. Due to this low incidence, they are considered rare diseases, and therefore few resources are set aside for their research.
Not all cells in the body are equally vulnerable to mitochondrial dysfunction: those with higher energetic needs tend to degenerate faster. As one of the organs consuming the most energy, the brain is one of the first to be affected and to a greater degree. In this sense, one of the most common and particularly severe symptoms is a form of epilepsy that does not respond to conventional treatments.
Now, in a new study published in The Journal of Clinical Investigation (JCI), a research team led by the Institut de Neurociències of the Universitat Autònoma de Barcelona was able to further investigate this type of epilepsy. By using mice models of Leigh syndrome, one of the most frequent mitochondrial diseases, researchers were able to investigate specific brain circuits and the neural alterations causing it.
Since epileptic crises involve excessive neural activation, the team 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. The scientists 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 Sánchez-Benito, researcher at the INc-UAB and first author of the study.
The team 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, the team discovered that the GPe GABAergic neurons are particularly vulnerable to mitochondrial dysfunction, which led to their generalised degeneration. 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 Sánchez-Benito 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”, affirms Professor Albert Quintana, coordinator of the study, and researcher at the INc-UAB and at the Department of Cell Biology, Physiology and Immunology at the UAB. “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.