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(Abst. 2.074), 2019

Characterization of an Experimental Mouse Model of Epilepsy-Associated Focal Cortical Dysplasia: Group Housing Video-EEG Wireless Telemetry Recordings
Authors: Natalia Rodriguez Alvarez, UCB Pharma; Veronique Marie Andre, UCB Pharma S.A; Lauren Drowley, UCB Pharma S.A; Martin Armstrong, UCB Pharma S.A; Stefanie Dedeurwaerdere, UCB Pharma S.A
Content: Rationale: Focal cortical dysplasia (FCD) is a group of localized cortical malformations responsible for focal epileptic seizures, which are highly refractory to current antiepileptic drugs. Emerging data have identified that an increased proportion of patients with FCD have mutations in the mTOR pathway, a crucial regulator of cell growth and survival. Many of these mutations are somatic and result in mosaicism in the brain, which has led to difficulties in understanding the functional consequences of these mutations. Therefore, experimental models of epilepsy-associated FCD are needed to develop effective treatments. Many experimental approaches to detect spontaneous seizures in mouse models of epilepsy are limited to adult animals and require single housing which constitutes a stressful situation and could interfere in experimental results. In addition, mutations in the mTOR pathway can synergize with other signaling pathways to influence social behavior. Since brain malformation disorders and epilepsy have also been linked with other neurodevelopmental outcomes such as autism spectrum disorders and cognitive deficits, it is important not only to exploit but also to be aware of environmental factors that may affect these experimental animal models. The goal of the present study was to extend the characterization of a developmental mouse model of epilepsy-associated FCD with a new group housing video-EEG wireless telemetry system and to investigate the presence of distinctive behavioral phenotypes in a social context.  Methods: We have evaluated a mouse model of epilepsy-associated FCD using in utero electroporation of mutations into the embryonic brain. Mutations involving genes at different points in the mTOR pathway were examined. In order to assess behavioral phenotypes in this model, we established a group housing video-EEG wireless telemetry platform that provides continuous recording of video-EEG 24 hours/day without supervision. Data was collected from cohabiting controls and FCD mice exercising free behavior.  Results: The model recapitulates the human pathophysiology of FCD. The abnormalities caused by mTOR activity upregulation lead to focal cortical disorganization, characterized by disrupted neural migration, cortical dyslamination and dysplastic neurons. Additionally, the model showed expression of in vivo epileptogenicity with manifestation of spontaneous and recurrent seizures starting at postnatal day 20 that closely resemble the dysplastic pathologies. The video-EEG wireless telemetry approach enabled unparalleled quality video-EEG recordings in real time in grouped-housed animals, with high sampling over extended periods of time. These recordings allowed us to identify specific behavioral patterns and EEG abnormalities in the model. FCD mice with recurrent seizures exhibit several symptoms of isolated-autistic like behavior, including reduced social interactions, freezing episodes and anxiety traits compared to control littermates.  Conclusions: This group housing video-EEG telemetry platform will allow us to investigate the presence of distinctive social behavioral phenotypes to evaluate potential adverse or beneficial effects of new drugs on animal behavior and establish a link between cortical malformations, epilepsy and neurodevelopmental comorbidities.  Funding: No funding