S-Ketamine Preserves Oxidative Metabolism and Reduces Metabolic Stress During Neuronal Hyperexcitability.

S-ketamine is increasingly used in anesthesia and neurocritical care and has been associated with anticonvulsant and potentially neuroprotective effects. Such neuroprotective effects have been observed particularly in states of severe hyperexcitability, including status epilepticus and spreading depolarizations, in which neuronal energy demand rises sharply and mitochondrial function may become compromised. However, the direct effects of S-ketamine on neuronal oxidative metabolism across different activity states remain incompletely understood. In acute hippocampal slices from 6-12-week-old male and female C57BL/6 mice, cerebral metabolic rate of oxygen (CMRO2) was quantified using depth-resolved tissue oxygen measurements under baseline conditions, during electrical stimulation, kainate-induced gamma oscillations, and Mg2+-free-induced epileptiform activity. Extracellular potassium dynamics and flavin adenine dinucleotide autofluorescence were recorded to assess neuronal excitability and mitochondrial redox state. S-ketamine was tested at concentrations of 100-1000 µM, and findings were integrated with computational modeling. At 100 µM, S-ketamine did not alter basal or stimulus-evoked CMRO2 or extracellular potassium handling. During gamma oscillations, S-ketamine modestly reduced CMRO2 and decreased oscillation frequency. Under Mg2+-free conditions, S-ketamine abolished seizure-like events and normalized CMRO2 to pre-Mg2+-free levels. Higher concentrations suppressed stimulus-evoked metabolism and attenuated mitochondrial redox responses, consistent with reduced neuronal activity rather than acute energy failure. These findings demonstrate an activity-dependent neurometabolic profile of S-ketamine characterized by preservation of oxidative metabolism under physiological conditions and reduced metabolic stress during pathological hyperexcitability.