Role of α7nAChR-NMDAR in sevoflurane-induced memory deficits in the developing rat hippocampus.

Xiaohong Tang,Jiying Ao,Yize Li,Ling Ding,Guolin Wang,Yang Liu,Yuan Yuan,Zhifen Wang,Michelle M Adams

doi:10.1371/journal.pone.0192498

Xiaohong Tang, Jiying Ao + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0192498

Copy DOI

Abstract

Detrimental effects of volatile anaesthetics, including sevoflurane, on the structure and function of the developing brain have been reported. The internalization of N-methyl-D-aspartate receptors (NMDARs) contributes to anaesthetic neurotoxicity. Both nicotinic acetylcholine receptors (nAChRs) and NMDAR play a critical role in the development of the nervous system. Moreover, nAChR can interact with NMDAR, and previous studies have demonstrated modulation of NMDAR by nAChR. In our study, we used an α7 nicotinic acetylcholine receptor (α7nAChR) agonist and α7nAChR antagonist to explore the role of α7nAChR and NMDAR in sevoflurane-induced long-term effects on memory and dendritic spine both in vivo and in vitro. The results revealed that the activation of α7nAChR attenuated the development of sevoflurane-induced memory deficit and dendritic spine changes, which might be by regulating NR2B-containing NMDAR trafficking from the intracellular pool to the cell surface pool in the hippocampus. Moreover, we demonstrated that α7nAChR could regulate NR2B-containing NMDAR via Src-family tyrosine kinase (SFK). Thus, our current study indicates that the trafficking of NR2B-containing NMDAR is regulated by α7nAChR via SFK in neonatal rat hippocampus, which may be secondary to sevoflurane-induced cognitive deficits in the developing hippocampus.

Highlights

The developing brain is vulnerable to general anaesthetic exposure, especially during critical stages, such as the peak of synaptogenesis that occurs during—the first two weeks after birth in rats, and from the 6th month of gestation to a few years after birth in human [1]
The increase in dendritic spine density and length by PNU was inhibited by PP2 (Fig 6A and 6B, P < 0.01, n = 8 per group). These results suggest that α7 nicotinic acetylcholine receptor (α7nAChR) can regulate NR2B-containing N-methyl-D-aspartate receptors (NMDARs) via Src-family tyrosine kinase (SFK) and that this molecular pathway may be involved in the changes in dendritic spine density and length
We showed that sevoflurane reduced the expression levels of α7nAChR and induced a significant increase in NMDA receptor subunits trafficking from the intracellular pool to the cell surface pool

Summary

Introduction

The developing brain is vulnerable to general anaesthetic exposure, especially during critical stages, such as the peak of synaptogenesis that occurs during—the first two weeks after birth in rats, and from the 6th month of gestation to a few years after birth in human [1]. Clinical studies have shown that anaesthesia and surgery exposure before age 3 may lead to learning disabilities and may increase the possibility of developmental delay or behavioural problems [2]. Sevoflurane, which is the most prevalently used inhalational anesthetic for paediatric patients, has been reported to lead to such impairments in animals [3,4]. Sevoflurane-induced memory deficits and α7nAChR-NMDAR data collection and analysis, decision to publish, or preparation of the manuscript

Objectives

Methods

Results

Conclusion