Ketamine causes mitochondrial dysfunction in human induced pluripotent stem cell-derived neurons

Area of Science:

• Neuroscience
• Toxicology
• Stem Cell Biology

Background:

• Ketamine toxicity is known in nonhuman mammals.
• Understanding ketamine's effects on human neurons is crucial.

Purpose of the Study:

• To investigate ketamine's toxic effects on human neurons.
• To elucidate the mechanism of ketamine neurotoxicity using an iPSC-derived model.

Main Methods:

• Cultured human iPSC-derived dopaminergic neurons were exposed to varying ketamine concentrations (0-500 μM) for 6 and 24 hours.
• Assessed caspase 3/7 activity, ROS production, mitochondrial membrane potential, ATP levels, neurotransmitter reuptake, and NADH/NAD+ ratio.
• Analyzed mitochondrial morphology using electron and confocal microscopy.

Main Results:

• High ketamine concentration (500 μM) increased caspase 3/7 activity and ROS, and reduced mitochondrial membrane potential.
• Lower ketamine concentration (100 μM) decreased ATP, increased NADH/NAD+ ratio, and induced mitochondrial fission and autophagocytosis.
• Mitochondrial dysfunction and autophagy were observed before ROS generation and caspase activation.

Conclusions:

• An in vitro model using iPSC-derived neurons was established to study ketamine neurotoxicity.
• Initial mitochondrial dysfunction and autophagy are implicated in ketamine neurotoxicity, potentially via inhibition of the mitochondrial electron transport system.
• Higher ketamine concentrations induce oxidative stress and apoptosis in human neurons.