Mechanizmy iktogeneze a epileptogeneze na podkladě vrozených vývojových vad mozku

Procházková, Natálie

Mechanisms of ictogenesis and epileptogenesis in epilepsy due to malformations of cortical development Abstract Focal cortical dysplasia type II (FCD II) represents one of the main causes of drug-resistant epilepsy in children and young adults, associated with somatic mutations that hyperactivate the mTOR pathway during cortical development. The causal links between structural abnormalities, cellular dysfunction, and epileptiform activity remain incompletely understood. The focus of this thesis is an investigation of ictogenesis and epileptogenesis mechanisms in FCD II using a novel mouse model. The theoretical part of the thesis describes the known histopathological, electrographic and genetic features of FCD II. To produce a faithful model, we created our own current-limited electroporator for safe in utero electroporation to induce focal lesions. Using patient-derived mTOR mutation, we produced FCD lesions reproducing key human FCD II hallmarks. Experimental part of the thesis includes detailed quantification of FCD II lesion structural and functional abnormalities studied using immunohistochemical staining, high-resolution microscopy, in vivo calcium imaging, and multichannel EEG. Ultrastructral changes of the lesion in seizing and non-seizing animals were studied together with high-frequency...

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