The role of the mitochondrial calcium uniporter in the control of neuronal network excitability and seizure susceptibility

Epilepsy affects approximately 70 million people worldwide and approximately 30% of those people develop refractory epilepsy, which cannot be controlled by the current available pharmaceutics. Refractory epilepsy increases a person’s risk for sudden unexpected death in epilepsy (SUDEP), which is the leading cause of death in epilepsy patients. Epilepsy is characterized by increased neuronal network excitability and an important aspect of neuronal network regulation are cytosolic Ca2+ levels. Neuronal cytosolic Ca2+ concentrations are regulated by mitochondria which efficiently buffer cytosolic Ca2+ and shape Ca2+ signals. Mitochondrial Ca2+ transport is controlled by a complex of proteins known as the mitochondrial Ca2+ uniporter (MCU) mediates mitochondrial Ca2+ uptake by forming a Ca2+ permeable channel. Deletion of MCU results in impaired Ca2+ uptake into mitochondria in neurons and significantly altered cytosolic Ca2+ signaling. Interestingly, we also found that global MCU deletion resulted in a profound anticonvulsant effect in in vitro epileptiform activity experiments, as well as in mice, where a maximal electroshock seizure threshold (MES) paradigm was used. Electrophysiological experiments revealed increased GABAergic synaptic activity and decreased excitatory synaptic activity in MCU-KO mice. To further determine if the anticonvulsant effect is driven by increased GABAergic signaling, we developed MCU floxed mice and crossed them with pan neuronal specific Synapsin-Cre, excitatory CaMKII-Cre and VGlut1-Cre, and inhibitory VGAT-Cre mice. We determined that pan neuronal and inhibitory neuron specific deletion of MCU resulted in increased MES thresholds, but excitatory specific deletion did not. Collectively, these experiments elucidate the mechanisms that underlie the robust anticonvulsant effects of MCU deletion. The results of these studies begin to provide insights into the role of mitochondrial Ca2+ transport in epilepsy and could guide the development of new therapeutic approaches targeting MCU and other mitochondrial Ca2+ transporters for treatment of epilepsy.