Glutamatergic Neurotransmission Links Sensitivity to Volatile Anesthetics with Mitochondrial Function

Area of Science:

• Neuroscience
• Anesthesiology
• Mitochondrial Biology

Background:

• The precise molecular mechanisms underlying volatile anesthetic (VA) action remain elusive despite over 150 years of research.
• While numerous molecular targets have been investigated, mitochondrial dysfunction has emerged as a key factor influencing VA sensitivity across species.
• Ndufs4 knockout (KO) mice, exhibiting a deficiency in mitochondrial complex I, display profound hypersensitivity to VAs, unlike their response to ketamine.

Purpose of the Study:

• To investigate the role of mitochondrial complex I deficiency in Ndufs4 KO mice on volatile anesthetic sensitivity.
• To determine the specific neuronal populations and synaptic mechanisms responsible for the observed hypersensitivity to volatile anesthetics.

Main Methods:

• Utilized Ndufs4 knockout (KO) mice and control littermates for comparative studies.
• Performed electrophysiological recordings (sEPSCs, sIPSCs, fEPSPs, PPF) in hippocampal CA1 pyramidal neurons.
• Investigated the effects of volatile anesthetics (isoflurane) at varying concentrations on neuronal activity.

Main Results:

• Ndufs4 KO mice exhibited significantly increased sensitivity to isoflurane compared to control mice.
• Reduced concentrations of isoflurane decreased spontaneous excitatory postsynaptic currents (sEPSCs) in Ndufs4 KO CA1 neurons, but not in controls.
• This hypersensitivity was recapitulated by limiting NDUFS4 loss to glutamatergic neurons, but not GABAergic or cholinergic neurons.
• No significant differences were observed in spontaneous inhibitory postsynaptic currents (sIPSCs) or evoked excitatory postsynaptic potentials (fEPSPs) between genotypes.

Conclusions:

• Presynaptic excitatory neurotransmission in the hippocampus is hypersensitive to volatile anesthetics in Ndufs4 KO mice.
• This hypersensitivity is attributed to the compromised mitochondrial complex I function, which impairs metabolic demands during anesthesia.
• The findings highlight a critical role for mitochondrial function in modulating volatile anesthetic effects, particularly at the level of excitatory neurotransmission.