Altered anesthetic sensitivity of mice lacking Ndufs4, a subunit of mitochondrial complex I

Abstract

Anesthetics are in routine use, yet the mechanisms underlying their function are incompletely understood. Studies in vitro demonstrate that both GABA(A) and NMDA receptors are modulated by anesthetics, but whole animal models have not supported the role of these receptors as sole effectors of general anesthesia. Findings in C. elegans and in children reveal that defects in mitochondrial complex I can cause hypersensitivity to volatile anesthetics. Here, we tested a knockout (KO) mouse with reduced complex I function due to inactivation of the Ndufs4 gene, which encodes one of the subunits of complex I. We tested these KO mice with two volatile and two non-volatile anesthetics. KO and wild-type (WT) mice were anesthetized with isoflurane, halothane, propofol or ketamine at post-natal (PN) days 23 to 27, and tested for loss of response to tail clamp (isoflurane and halothane) or loss of righting reflex (propofol and ketamine). KO mice were 2.5 - to 3-fold more sensitive to isoflurane and halothane than WT mice. KO mice were 2-fold more sensitive to propofol but resistant to ketamine. These changes in anesthetic sensitivity are the largest recorded in a mammal.

Figure 1. EC₅₀s for isoflurane (ISO) and halothane (HAL) to cause immobility in response to tail pinch.

Dark bars show the EC₅₀s for wild-type (WT) mice (n = 10, ISO; n = 6, HAL); open bars show the values for the Ndufs4 KO mice (n = 10, ISO; n = 6, HAL). Error bars show the standard deviations. The values for the KO animals were significantly different from those for WT with a p<0.01.

Figure 2. The dose response curves for WT and Ndufs4 KO mice for LORR after intraperitoneal propofol.

Dose-response curves were generated using the percentage of mice that presented LORR at the measured concentrations (n = 5–7 per group for each injection dose). The values for the KO animals were significantly different from those for WT (p<0.01).

Figure 3. The dose response curves for WT and Ndufs4 KO mice for LORR after given intraperitoneal ketamine.

Dose-response curves were generated using the percentage of mice that presented LORR at the measured concentrations (n = 5–7 per group for each injection dose). The values for the KO animals were significantly different from those for WT (p<0.01).