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

Epilepsy is a condition that affects approximately 70 million people worldwide and is defined by the presence of chronic seizures. Approximately 30% of epilepsy patients develop refractory epilepsy which is epilepsy that cannot be controlled with current pharmaceutical treatments. Further investigation is required to identify therapies for patients with refractory epilepsy. The mitochondrial calcium uniporter (MCU) is the pathway responsible for calcium uptake by mitochondria, which are the energy producing components of neurons. It is not well understood how MCU plays a role in neuronal function. We used mice with the MCU gene deleted (MCU-KO) to examine how MCU affects different aspects of nervous system functions. We first discovered that neurons cultured from MCU-KO mice were less affected by drugs that are known to cause seizure activity in mice. We then observed that MCU-KO mice were more resistant to induction of generalized seizures. We next discovered that MCU-KO neuron networks have increased inhibitory activity and reduced excitatory activity as compared to normal neuron networks. We then investigated if MCU deletion in only inhibitory neurons recapitulated the anticonvulsant effects we observed in whole body MCU-KO mice and found a similar albeit weaker anticonvulsant effect, which was not recapitulated in excitatory neuron deletion of MCU. These studies will provide a mechanistic insight into the anticonvulsant effects of MCU deletion and determine the specific role of inhibitory neurons in this process. They will also shed light on the role of mitochondrial calcium transport in regulating neural network activity and excitability.