Sevoflurane inhibits neuronal migration and axon growth in the developing mouse cerebral cortex.

Dongdong Chai,Hong Jiang,Yu Sun,Jia Yan,Chunzhu Li

doi:10.18632/aging.103041

Abstract

The highly organized laminar structure of the mammalian brain is dependent on successful neuronal migration, and migration deficits can cause lissencephaly and behavioral and cognitive defects. Here, we investigated the contribution of neuronal migration dysregulation to anesthesia-induced neurotoxicity in the fetal brain. Pregnant C57BL/6 mice at embryonic day 14.5 received 2.5% sevoflurane daily for two days. Cortical neuron migration and axon lengths were evaluated using GFP immunostaining. Morris water maze tests were performed to assess the effects of sevoflurane exposure on spatial memory in offspring. We found that sevoflurane exposure decreased axon length and caused cognitive defects in young mice. RNA sequencing revealed that these defects were associated with reduced neuro-oncological ventral antigen 2 (Nova2) expression. In utero electroporation experiments using Nova2 shRNA recapitulated this finding. Nova2 shRNA inhibited neuronal migration and decreased axon lengths. Finally, we found that Netrin-1/Deleted in Colorectal Cancer (Dcc) proteins acted downstream of Nova2 to suppresses neuronal migration. These findings describe a novel mechanism by which prenatal anesthesia exposure affects embryonic neural development and postnatal behavior.

Highlights

To decrease the risk of spontaneous abortion and preterm labor, any surgery required by a pregnant woman is typically delayed until the second trimester when most of the physiological changes in the fetus have reached a plateau and anesthesia is relatively safer [1]
Using a Nikon A1 fluorescence microscope equipped with a 20x objective to trace axonal length, we found that dual sevoflurane exposure in midgestation significantly decreased the axon length (Figure 1C, 1D, P = 0.0147, N = 3, Student’s t-test)
We previously www.aging-us.com found that dual sevoflurane exposure can lead to cognitive dysfunction in young animals, while single short or long duration exposure didn’t affect spatial learning, suggesting that fetuses were vulnerable to dual exposure

Summary

Introduction

To decrease the risk of spontaneous abortion and preterm labor, any surgery required by a pregnant woman is typically delayed until the second trimester when most of the physiological changes in the fetus have reached a plateau and anesthesia is relatively safer [1]. Protection of fetal development in utero is the prime concern for most parents when anesthesia is required for surgical procedures [2]. The second trimester is a critical period for development of the embryonic nervous system: neurogenesis, neuronal migration, and corticogenesis are the major neurodevelopmental events that occur at this stage [3]. Neuronal migration plays an important role in nervous system formation and in neuronal development and activity [4]. Even a relatively nonintrusive operation such as abdominal ultrasonography can cause fetal neuronal migration deficits [6]. Maternal ethanol ingestion can prevent neurons from migrating to the cortex and can impair cortical formation during embryonic development, leading to behavioral abnormalities [7]. We have found that dual sevoflurane exposure can inhibit neuronal migration in offspring [8]; whether and how dual sevoflurane exposure affects spatial learning in those offspring remains unknown

Methods

Results

Conclusion