Research reportThe decrease of NMDAR subunit expression and NMDAR EPSC in hippocampus by neonatal exposure to desflurane in mice
Introduction
For decades, used alone or as a part of balanced anesthesia, inhalation anesthetics have been the most widely administered drugs in most anesthesia communities. However, several preclinical reports have demonstrated that inhalation anesthetics are neurotoxic to the neonatal brains in mice [1], [2], rats [3], [4], [5], [6] and primates [7]. Those data obtained in newborn animals have raised serious safety concern regarding current inhalation anesthetics practice in young children. Desflurane is one of the latest inhaled anesthetics and can be used in obstetric and pediatric medicine. However, the effect of neonatal exposure to desflurane is still largely unknown.
The N-methyl-d-aspartate receptor (NMDAR), a major class of ionotropic glutamate receptors, is considered to be crucially involved in synaptic plasticity and neurogenesis in the neonatal brain [8], [9]. Functional NMDARs are heteromultimers formed by the assembly of the NR1 and NR2 subunits. Recently, several lines of evidence have suggested that abnormal levels of NMDAR subunits NR1, NR2A and NR2B protein expression in the neonatal brain correspond to memory dysfunction performance [10], [11], [12]. As NMDAR is one of molecular targets of anesthetics [13], NMDAR may play an important role in anesthesia induced cognitive deficits in the neonatal brain. Therefore, it is beneficial to study the effect of desflurane anesthesia on neonatal brain from the perspective of NMDAR.
The present study aims to investigate the effect of desflurane anesthesia on the neonatal mice brain, and the underlying mechanism of side effect on the NMDAR. To address this issue, 6-day-old mice were exposed to a clinically relevant concentration of desflurane, and then behavioral tests were performed to evaluate learning and memory of mice when they were 28-day-old. Moreover, the level of NMDAR protein expression and NMDAR-mediated excitatory postsynaptic current (EPSC) in hippocampus were evaluated when the mice were 28-day-old.
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Animals
All experiments were conducted according to the institutional ethical guidelines for animal experiments of Tianjin Medical University and were approved by the Committee for Animal Research at Tianjin Medical University (Tianjin, China). The C57BL/6J mice (both male and female) used in this study were maintained on a 12 h light-dark cycle with room temperature at 22° ± 1 °C. Mice had ad libitum access to water and food.
Experiment protocol
To investigate the effects of 1 minimum alveolar concentration (MAC) or 1.5 MAC
Arterial blood gas analysis
Because the administration of desflurane anesthesia could produce hemodynamic instability leading to hypoxic injury, we examined the blood gas data in mice during the anesthesia. Control samples were obtained from control group during the same period. pH, Pao2, and Paco2 values in two desflurane groups were within the normal physiologic range and no significant difference was found compared with the control group(shown in Table 1).
General behaviors were normal in mice with neonatal exposure to 1 MAC or 1.5 MAC desflurane
To examine behavioral activity in a novel environment, mice from
Discussion
In this study, we observed that 6-day-old mice exposed to 1.5 MAC desflurane had significant impairment in working memory and contextual fear memory at postnatal day 28. Meanwhile, the protein expression of NR1, NR2B subunits and NMDAR-mediated EPSCs in the hippocampus were significantly decreased.
Neurotransmitter-gated ion channels, in particular NMDA and GABAA receptors, are regarded as the most likely molecular targets for general anesthetics. NMDAR has essential physiological roles in
Conflict of interests
The authors have no conflict of interest to declare.
Author contributions
G.W. and H.S. designed the study; X.X, C.Z. and N.L. performed the experiments and developed the data analysis. All of the authors discussed the data and co-wrote the paper.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (NSFC 81471393, 61301252, 81371245 and 81571077), Science and Technology Supported Key Project of Tianjin (12ZCZDSY03000), China Postdoctoral Science Foundation funded project (2014M561193), the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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These authors contributed equally to this work.