The Role of Neuronal Mitochondrial ca2+ Uniporter (MCU) in Seizure Susceptibility
Abstract number :
3.08
Submission category :
1. Basic Mechanisms / 1E. Models
Year :
2024
Submission ID :
239
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Tam Nguyen, BS – University of Iowa
Grant Walters, PhD – University of Iowa
Jacob Rysted, PhD – University of Iowa
Benton Purnell, PhD – Rutgers University
Zhihong Lin, PhD – University of Iowa
Stefan Strack, PhD – University of Iowa
Gordon Buchanan, MD, PhD – University of Iowa
Yuriy Usachev, PhD – University of Iowa
Rationale: Epilepsy is a neurological disorder marked by the presence of chronic seizures. It poses tremendous public health challenges due to its impact on patients and society. While epileptic seizures can be managed through pharmaceutical therapies, about one-third of patients with epilepsy may develop refractory epilepsy which is associated with increased risk of sudden unexpected death in epilepsy (SUDEP), the leading cause of mortality in epilepsy patients. Thus, there is a critical need to develop targeted therapeutics for patients with refractory epilepsy. The mitochondrial calcium uniporter (MCU) is a highly conserved pore-forming subunit of the MCU complex that mediates Ca2+ uptake into the mitochondrial matrix.
Methods: Here, we examined the role of neuronal mitochondrial Ca2+ transport in regulating neural hyperexcitability and seizures in acute and chronic models.
Results: Deletion of MCU resulted in impaired Ca2+ uptake into mitochondria in neurons, inhibited mitochondrial Ca2+ dysregulation and excitotoxicity in brain mitochondria. Extensive behavioral testing did not detect any significant changes in sensory, motor, or cognitive functions in MCU knockout mice compared to wildtype mice. We found that MCU deletion prevents the induction of epileptiform activity by chemo-convulsant agents in vitro. In a model of maximal electroshock-induced (MES) seizures, global MCU deletion in mice (CD1 background) produced strong anticonvulsant effects. Furthermore, neuron-specific deletion of MCU (C57BL/6 background) significantly increased the threshold of seizure induction, and markedly reduced severity of seizures. We also observed changes in the effect of neuron-specific deletion of MCU in the mortality rates and the onset and frequency of spontaneous recurrent seizures using the pilocarpine model of temporal lobe epilepsy.
Conclusions: Our findings indicate that MCU could represent an attractive novel molecular target for the development of new anticonvulsant therapeutics.
Funding: This research was supported by the National Institutes of Health under award number NS125884 and NS127428.
Basic Mechanisms