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Friday, September 28 2018
Press release

A new therapeutic target to control epileptic seizures

A naturally occurring compensatory mechanism in epilepsy could potentially be sought early for therapeutic purposes.

MONTREAL, September 28, 2018 – Epileptogenic encephalopathies – i. e. severe forms of epilepsy marked by developmental stagnation, intellectual disability or sometimes autism – occur very early in a child's development. These conditions are generally resistant to treatment and are even lethal during childhood. A study conducted by researchers at CHU Sainte-Justine and Université de Montréal establishes a new therapeutic target to control motor seizures in two preclinical models of the disease, which in the medium term could improve anti-epileptic treatment options and survival chances for patients with the disease. "Everything happens at the level of different subtypes of GABAergic interneurons that, as their name suggests, are located between the excitatory neurons and make it possible to inhibit these neurons through the release of GABA," says Alexis Lupien-Meilleur, MSc, co-first author of the study. In practical terms, by selectively activating a specific subtype of interneurons, the somatostatin interneurons, researchers believe they can prevent tonic-clonic or grand mal seizures, as these interneurons can play a key role in cortical inhibition. The results of the study are reported in an article published in the journal Annals of Neurology.

"Poorly controlled motor seizures in epilepsy can unfortunately lead to an increased risk of accident during an attack and even unexpected sudden death in some forms of the disease. Here, we have observed a new therapeutic pathway for children with epileptogenic encephalopathy with treatment-refractory epilepsy and cognitive disorders, particularly those whose condition is due to mutations in the CACNA1A gene," adds Alexis Lupien-Meilleur. It should be noted that half of all cases of epileptogenic encephalopathies are caused by genetic abnormalities. Mutations in the CACNA1A gene explain about 1% of them and are also associated with isolated forms of autism, intellectual disability or attention deficit, as previously demonstrated by the research team of Dr. Elsa Rossignol, a neuropediatrician specializing in neurogenetics, researcher at CHU Sainte-Justine and lead author of the study.

The biological factors determining the type and severity of epileptic seizures in patients with epileptogenic encephalopathy are still poorly understood and the potential adverse impact of some drugs remains uncertain. "Although epileptogenic encephalopathies sometimes reflect an imbalance between excessive excitation or cortical inhibition failure, we have suggested that the various forms of inhibition may contribute differentially to the clinical manifestations of the disease and that it is possible to selectively manipulate specific types of interneurons, or those expressing somatostatin, to prevent motor seizures and better treat epilepsy, rather than providing generic treatments," explains Dr. Rossignol.

Indeed, deleterious mutations of the CACNA1A gene lead to epileptic seizures of the absence type and tonic-clonic seizures that fade with age due to a paradoxical gain in cortical inhibition. This gain in inhibition reflects a remodeling of somatostatin-expressing interneurons, a subtype of inhibitory interneurons that target pyramidal cell dendrites, the excitatory cells of the cortex. This gain in dendritic inhibition prevents the cortical spread of epileptic activity, also preventing the development of tonic-clonic motor seizures. "We have demonstrated that this remodelling is dependent on the mTOR intracellular signalling pathway that plays a key role in the inner balance of cells, and that its removal by mTOR modulator blocker treatment aggravates and multiplies epileptic seizures. In addition, we have established that selective stimulation of somatostatin interneurons prevents motor seizures. Our work reveals, for the first time, the central role of dendritic inhibition of pyramidal cells in a pathological context and some of the compensatory mechanisms that occur naturally over time, but can potentially be used early for therapeutic purposes," says Dr. Rossignol.

The results generated by this study will provide a better understanding of the mechanisms underlying the development of epilepsy and cognitive disorders in this genetic disease in children. In the medium term, these results could lead to the development of targeted therapies to better control epilepsy seizures.  In addition, although mTOR inhibitor drugs have recently been suggested as good modulating treatments in epilepsy, for example in cases of tuberous sclerosis associated with overactivation of the mTOR signalling pathway, these results suggest that their indiscriminate use in patients whose primary pathology does not involve mTOR overactivity could have adverse effects by preventing some beneficial compensatory phenomena.

"We are continuing our research to develop translational methods to selectively activate certain targeted neural populations, rather than all circuits indiscriminately as current systemic medications do," concludes Dr. Rossignol.

About the study

The article titled "Remodeled cortical inhibition prevents motor seizures in generalized epilepsy" was published online in the journal Annals of Neurology in August 2018. The co-first authors are Xiao Jiang, MD, PhD, postdoctoral fellow and Alexis Lupien-Meilleur, MSc, PhD student, both under the supervision of Elsa Rossignol, MD, MSc. The principal author is Elsa Rossignol, a neuropediatrician specializing in neurogenetics. She is a researcher and Deputy Head, Research Axis, Brain and Child Development at CHU Sainte-Justine and Clinical Assistant Professor in the Department of Neurosciences at Université de Montréal. This study was carried out in collaboration with the laboratories of Professors Jean-Claude Lacaille and Roberto Arraya in the Department of Neurosciences at Université de Montréal. This work was supported by the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC), the Fonds de recherche du Québec - Santé (FRQS) and the Fondation Savoy.

Authors: Xiao Jiang, MD, PhD; Alexis Lupien-Meilleur, MSc; Sabrina Tazerart, PhD; Mathieu Lachance, MSc; Elena Samarova, PhD; Roberto Araya, PhD; Jean-Claude Lacaille, PhD and Elsa Rossignol, MD, MSc

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About the CHU Sainte-Justine Research Center

CHU Sainte-Justine Research Center is a leading mother-child research institution affiliated with Université de Montréal. It brings together more than 200 research investigators, including over 90 clinician scientists, as well as 450 graduate and postgraduate students focused on finding innovative prevention means, faster and less invasive treatments, as well as personalized approaches to medicine. The Center is part of CHU Sainte-Justine, which is the largest mother-child center in Canada and second pediatric center in North America. More at research.chusj.org

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CHU Sainte-Justine
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Maude Hoffmann
Communications, CHU Sainte-Justine Research Center
communications@recherche-ste-justine.qc.ca

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Patsy Coulanges
CHU Sainte-Justine
Office: 514-345-4931, ext. 4354
patsy.coulanges.hsj@ssss.gouv.qc.ca

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Updated on 9/28/2018
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