Authors :
Presenting Author: Jakub Otáhal, MD, PhD – Institute of Physiology, Czech Academy of Sciences
Jan Daněk, Bc – Institute of Physiology, Czech Academy of Sciences; Jan Svoboda, MSc. – Institute of Physiology, Czech Academy of Sciences; Petr Pecina, PhD – Institute of Physiology, Czech Academy of Sciences; Peter Buran, MSc. – Institute of Physiology, Czech Academy of Sciences; Šárka Danačíková, MSc – Institute of Physiology, Czech Academy of Sciences; Kateřina Macková, Ing. – Faculty of Electrical Engeneering, Czech Technical University; Radek Janča, PhD – Faculty of Electrical Engeneering, Czech Technical University; Tomáš Mráček, PhD – Institute of Physiology, Czech Academy of Sciences; Martin Balaštík, PhD – Institute of Physiology, Czech Academy of Sciences; Přemysl Jiruška, Prof. – 2nd Faculty of Medicine, Charlues University
Rationale:
Epilepsy is particularly frequent in infants and children where it can lead to serious consequences later in life, such as adverse effects on brain maturation, and various cognitive deficits, especially those affecting learning and memory. The treatment of epilepsy is long-term and it represents a substantial financial burden. Current pharmacotherapies are mostly symptomatic and ineffective in 30% of patients. Patients with pharmacoresistant epilepsy may profit from surgical removal of the tissue responsible for seizure initiation. Identification of epileptic focus relies on multimodal neuroimaging and electrophysiology. Functional neuroimaging methods consistently revealed altered glucose metabolism and vascular dysregulation in epileptic focus. Although disturbances in energy metabolism on a cellular level as well as in vascular reactivity have been documented in chronic epileptic tissue from both experimental models and human surgeries the causal relationship between them and their contribution to the development of epilepsy and neuroimaging findings is far from being clear. Nevertheless, regardless of the type and cause of epilepsy, "hypometabolism” on interictal FDG PET is the most predictive factor for surgery outcome. Elucidation of mechanisms involved would first clarify causal relations between energy metabolism, neurovascular coupling, and epilepsy itself and second improve diagnostic and treatment pipelines, which can finally improve the quality of life of patients with intractable epilepsies. The aim of the study was to elucidate alterations in energy metabolism inside epileptogenic lesion in a mice model of Focal Cortical Dysplasia (FCD).
Methods:
FCD with morphology IIb was experimentally modeled by in utero electroporation of mTOR mutation (p.Leu2427Pro) that has been identified as causative of human FCD, into embryonic mouse brains. Briefly, the cDNA construct containing the p.Leu2427Pro mutation together with a gene for green fluorescent protein (GFP) was injected into the lateral ventricle of E14 mouse embryos and electroporated. We reproducibly observe impacts on cortical development and the occurrence of pathological neuronal morphologies analogous to the dysplastic cortex observed in human FCD IIb. Controls obtained the same procedure and only GFP plasmid were electroporated. After four to six months animals underwent 18F-DG PET scanning to reveal glucose uptake and then the lesion and control tissues were harvested for assessment of respiration. The respiration of the tissue was evaluated with standard Oxygraph protocol.
Results:
Animals with electroporated mTOR mutation revealed significant glucose hypometabolism inside FCD lesion on partial volume corrected 18F-DG PET. Control and wild-type animals did not possess any signal alterations throughout the brain. Oxygraph revealed a significant reduction of respiration within the FCD lesion in comparison to both control and wild-type tissue.
Conclusions:
In conclusion, our data clearly demonstrate alterations in both glucose uptake and oxidative metabolism in the FCD lesion caused by human mTOR mutation in mice model.
Funding:
The study was funded by grants of Czech Science Foundation numbers 22-28265S and 21-17564S.