Neuroinflammation and cellular alteration in mTORopathies From neuropathology to complex in-vitro models

Epilepsy is a common neurological disorder affecting over 50 million individuals worldwide. The resulting epilepsy syndromes are characterized by significant societal impact and associated neurobiological comorbidities. The process of epileptogenesis, the formation of an epileptic network, lays at the foundation of this disease. In this thesis, we focused on a subgroup of epileptic disorders collectively known as mTORopathies, with a focus on tuberous sclerosis complex (TSC) and the pathologically-similar focal cortical dysplasia (FCD). Due to the nature of the pathology, its characteristic neurological lesions and other alterations, patients often suffer from high degrees of intractable epilepsy, autism spectrum disorder and intellectual disability. Our understanding of this process, especially in the early stages of development, remains limited. Aberrant neural networks found in and around lesions can be influenced by glial cells and modulated through inflammation-related molecules such as cytokines and the complement system. In this thesis, we aimed to broaden our understanding of inflammatory pathways in TSC and FCD, including alterations in adhesion molecule CNTN3 and loss of homeostatic functions in TSC. To investigate the early stages of disease development and network modulation in the brain, we developed and characterized a patient-derived induced pluripotent stem cell (iPSC) tri-culture system. This system produced an electrically maturing network that incorporated pathological hallmarks.