Understanding cellular and molecular bases of drug resistance in EPIlepsy: a translational researCh on hUman bRain samplEs and clinical data

Epilepsy is one of the most common and disabling neurological disorders, affecting more than 6M European patients and with 300,000 new cases diagnosed every year. All currently available anti- seizure medications (ASMs) are not specific enough and often have significant side effects, including cognitive and psychiatric disturbances. One third of the patients is expected to develop drug- resistance throughout their disease course, with high risk of associated co-morbidities and mortality. This emphasizes the need of patient-tailored protocols to predict drug efficacy or adverse events and the need to develop highly efficient drugs, targeting specifically those neurons that contribute to epilepsy. Current ASMs target mechanisms controlling neuronal excitability or synaptic transmission, but their efficacy remains limited due to the complex nature of epilepsy pathophysiology. Here we propose an innovative multimodal translational approach [Fig. 1 in the attachment] to investigate the electrophysiological properties of live human brain tissues to tackle the cellular and molecular bases of DRE. Relying on an ongoing close collaboration between clinicians and researchers, our team will combine routine clinical procedures and preoperative medical data collection with disease-motivated basic research that will boost unprecedented discoveries paving the way for personalized therapeutic interventions. Our project combines i) preoperative EEG and intraoperative ECoG electrophysiological recordings ii) multiple patch-clamp intracellular recordings; iii) high-resolution microelectrode array (HD-MEA); iv) an informatic standardized pipeline generating a robust and exhaustive readout of the electrophysiological data gaining insights into DRE etiopathology. - Patch-clamp recordings will allow to investigate alterations in intrinsic neuronal excitability, synaptic transmission and synaptic connectivity patterns - HD-MEA will enable a high resolution spatio-temporal investigation of the network activity in control condition or following drug perfusion - Preoperative and intraoperative EEG and ECoG data will be linked to cellular level data through an informatic standardized workflow endowed with advanced bioelectrical signal processing methods. This ambitious approach aims at identifying the abnormal activity of ion channels, receptors, or signaling pathways that are altered in DRE and fail to respond to known compounds. DRE-induced alterations will be compared to properties of: a) brain tissue removed from patients with lesional drug-responsive epilepsy (i.e. ganglioglioma, low-grade glial tumors); b) non epileptic tumor access tissues in patients with brain gliomas. Our findings will significantly advance our understanding of the cellular and molecular mechanisms underlying DRE, providing in the long-term a foundation for personalized medicine approaches in epilepsy treatment that ultimately lead to the development of novel therapeutic strategies.