Paroxysmal depolarization protects neurons via mitochondria

Acquired epilepsy is the most common form of epilepsy in the adult population. The disease is triggered by an injury to the brain, followed by a prolonged asymptomatic phase of epileptogenesis during which neuronal processes occur that make the brain susceptible to epileptic seizures. There is currently no strategy to prevent the development of epilepsy. The available treatments are aimed at controlling seizures; therefore, the disease is only treated symptomatically. The silent phase of epileptogenesis represents a potential therapeutic window for intervention to suppress seizure development. Understanding the underlying neuronal processes leading to epilepsy development is essential for the development of a future strategy. A hallmark of ongoing epileptogenesis are interictal spikes (IS), which are measured by EEG in the scalp of epilepsy patients. IS are caused by synchronous electrical firing of a large group of neurons, this firing is called paroxysmal depolarization shifts (PDS). In the current project, we want to investigate the effects of PDS on neuronal metabolism. Our data suggest that PDS induce a metabolic switch that causes neuronal mitochondria to utilize less glucose and more glutamine, and that this metabolic switch protects neurons from the deleterious effects of neuronal hyperexcitability. Understanding of the details of PDS-induced metabolic switch can therefore lead to a neuroprotective strategy and possibly shed light on the mechanism of epileptogenesis. In this project, we will map neuronal glucose and glutamine metabolism in detail using state-of-the-art live-cell microscopy and metabolomics techniques. The data obtained will be supplemented by measurements of neuronal activity and viability tests. The research will be conducted by Dr. Matej Hotka and one doctoral student jointly at the Karl Landsteiner Private University of Health Sciences in Krems an der Donau and Center for Physiology and Pharmacology of the Medical University of Vienna. The research will greatly benefit from the expertise of Drs. Helmut Kubista and Stefan Boehm from the Center for Physiology and Pharmacology at the Medical University of Vienna (MUV), Dr. Thomas Koecher (Head of the Metabolomics Core Facility at the Vienna Biocenter) and Dr. Roman Romanov from the Center for Brain Research MUV. The multidisciplinary approach of this research project will lead to results that will shed light on the previously controversial role of PDS in epileptogenesis.