Astroglial dysfunctions drive aberrant synaptogenesis and social behavioral deficits in mice with neonatal exposure to lengthy general anesthesia

Zhou, Bin; Chen, Lingmin; Liao, Ping; Huang, Lu; Chen, Zhuo; Liao, Daqing; Yang, Linghui; Wang, Jing; Yu, Guoqiang; Wang, Li; Zhang, Jianguo; Zuo, Yunxia; Liu, Jin; Jiang, Ruotian

doi:10.1371/journal.pbio.3000086

Cited by 59 publications

(68 citation statements)

References 53 publications

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“…Both excitatory and inhibitory synaptic inputs have been shown to be regulated by sevoflurane during postnatal development. Lengthy sevoflurane exposure at P7 has been reported to compromise astrocyte development, which arrests excitatory synapse maturation and results in decreased mEPSC frequency in cortical pyramidal neurons 41 . Long-term reduction in excitatory inputs may cause homeostatic scaling of excitatory synapses a and indirectly enhance neuronal excitability.…”

Section: Discussionmentioning

confidence: 99%

Neonatal sevoflurane exposure induces impulsive behavioral deficit through disrupting excitatory neurons in the medial prefrontal cortex in mice

Xie

Liu

et al. 2020

Transl Psychiatry

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Sevoflurane, in particular multiple exposures, has been reported to cause the abnormal neurological development including attention-deficit/hyperactivity disorder (ADHD). This study is to investigate ADHD-like impulsivity in adult mice after repeated sevoflurane exposures at the neonatal stage. Six-day-old pups were exposed to 60% oxygen in the presence or absence of 3% sevoflurane for 2 h and the treatment was administrated once daily for three consecutive days. To assess the impulsivity, the cliff avoidance reaction (CAR) was carried out at the 8th week. Our results showed that repeated sevoflurane treatment increased the number of jumps and shortened the jumping latency in the CAR test. The cortices were harvested for immunostaining to detect c-Fos and calmodulin-dependent protein kinase IIα (CaMKIIα) expression in the medial prefrontal cortex (mPFC). We found that mPFC neurons, especially excitatory neurons, were highly activated and related to impulsive behavior. The activation viruses (AAV-CaMKIIα-hM3Dq) were injected to evaluate the effects of specific activation of mPFC excitatory neurons on impulsive behavior in the presence of clozapine-N-oxide (CNO). Likewise, the inhibitory viruses (AAV-CaMKIIα-hM4Di) were injected in the sevoflurane group to explore whether the mPFC excitatory neuronal inhibition reduced the impulsivity. Our results revealed that chemogenetic activation of mPFC excitatory neurons induced impulsive behavior whereas inhibition of mPFC excitatory neurons partially rescued the deficit. These results indicate that repeated sevoflurane exposures at the critical time induce impulsive behavior accompanied with overactivation of mPFC excitatory neurons in adult stages. This work may further extend to understand the ADHD-like impulsive behavior of the anesthetic neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

Neonatal sevoflurane exposure induces impulsive behavioral deficit through disrupting excitatory neurons in the medial prefrontal cortex in mice

Xie

Liu

et al. 2020

Transl Psychiatry

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“…Thus, any adverse external intervention factors including anesthetics can affect the development of the embryonic brain. Recently, Zhou (2019) have shown that sevoflurane drove aberrant synaptogenesis and social behavioral deficits in neonatal mice by disrupting astrocyte Ca 2+ homeostasis which induced astroglial dysfunctions. ZO‐1, also known as tight junction protein‐1, and postsynaptic density‐95 (PSD‐95) were important protein markers of neurogenesis and synaptogenesis in the central nervous system (Beck‐Schimmer et al, 2020; Park et al, 2015).…”

Section: Sevoflurane and Neurogenesismentioning

confidence: 99%

Prenatal sevoflurane exposure: Effects of iron metabolic dysfunction on offspring cognition and potential mechanism

Zuo

Chang

Thirupathi

et al. 2020

Intl J of Devlp Neuroscience

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For decades, the neurotoxicity caused by anesthetics in mammalian brain development has gained increasing attention. Exposure to anesthetics leads to neurotoxicity and apoptosis of nerve cells, which in turn induces cognitive dysfunction. Although most of the data came from animal studies, general anesthetics have been shown to have adverse effects on cognitive function in infants and young children in recent years. This concern has led to a number of retrospective studies that observed an association between general anesthesia in pregnant women and neurobehavioral problems in fetuses or offspring. Every year, many pregnant women undergo non‐obstetric anesthesia due to various reasons such as traffic accidents, fetal interventions, acute appendicitis, symptomatic cholelithiasis, and trauma. A matter of concern for these pregnant women is whether anesthesia has a detrimental effect on fetal brain development in the womb and whether the fetus has cognitive impairment after birth. In humans, the association of anesthetic exposure in infants with the long‐term impairment of neurologic functions has been reported in several retrospective clinical studies. Recently, we have found that sevoflurane anesthesia during pregnancy in mice‐induced cognitive impairment in the offspring by causing iron deficiency and inhibiting myelinogenesis. Sevoflurane is a commonly used general anesthetic in the hospitals, which can induce neurotoxicity and cause cognitive impairment in fetuses, infants, children, and adults. However, the exact mechanism of sevoflurane‐induced damage to the central nervous system (CNS) is not fully understood. Based on our recent results, this paper reviewed the effects of sevoflurane on cognitive impairment and pathological changes such as neurogenesis, neuronal apoptosis, and iron metabolism dysfunction in the offspring.

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“…If molecular structure changes, it will have an effect on the learning and memory ability [1,2]. There are many reports stating that long-term, repeated, or high-dose sevoflurane anesthesia in neonatal rats can cause changes in nervous system function and affect the long-term learning and memory and cognitive function [3][4][5]. The FDA warned that repeated or prolonged (more than 3 h) use of anesthetics and sedatives may impair the brain of fetus and children less than 3 years [6].…”

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine Attenuates Neurotoxicity in Developing Rats Induced by Sevoflurane through Upregulating BDNF-TrkB-CREB and Downregulating ProBDNF-P75NRT-RhoA Signaling Pathway

Dong

Hong

Tang

et al. 2020

Mediators of Inflammation

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To investigate the mechanism dexmedetomidine in relieving the neurotoxicity of a developing brain induced by sevoflurane. Sprague-Dawley rats, 6 days old, were randomly divided into three groups. Rats in the control group were inhaled with air after injection of normal saline; rats in the sevoflurane group were injected with normal saline and inhaled with 3% sevoflurane for 2 h in three consecutive day; rats in the dexmedetomidine group were inhaled with 3% sevoflurane after intraperitoneal injection of dexmedetomidine 25 μg/kg. WB results showed that mBDNF, pTrkB/TrkB, and CREB were significantly decreased in the hippocampus of the sevoflurane group, which are significantly upregulated in the dexmedetomidine group. In the sevoflurane group, proBDNF, P75NRT, and RhoA were significantly increased, which were significantly lower than those in the dexmedetomidine group than those in the sevoflurane group. The expression BDNF was downregulated in the sevoflurane group, while the proBDNF was upregulated in the sevoflurane group. In the Morris water maze test, the escape latency of the sevoflurane group was significantly prolonged. In sevoflurane groups, the number of crossing platform was significantly reduced, the synaptic protein decreased significantly, and this effect was reversed in rats of the dexmedetomidine group. Dexmedetomidine could reduce synaptic plasticity decline in developing rats induced by sevoflurane, through downregulating the proBDNF-p75NTR-RhoA pathway and upregulating BDNF-TrkB-CREB.

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Astroglial dysfunctions drive aberrant synaptogenesis and social behavioral deficits in mice with neonatal exposure to lengthy general anesthesia

Cited by 59 publications

References 53 publications

Neonatal sevoflurane exposure induces impulsive behavioral deficit through disrupting excitatory neurons in the medial prefrontal cortex in mice

Neonatal sevoflurane exposure induces impulsive behavioral deficit through disrupting excitatory neurons in the medial prefrontal cortex in mice

Prenatal sevoflurane exposure: Effects of iron metabolic dysfunction on offspring cognition and potential mechanism

Dexmedetomidine Attenuates Neurotoxicity in Developing Rats Induced by Sevoflurane through Upregulating BDNF-TrkB-CREB and Downregulating ProBDNF-P75NRT-RhoA Signaling Pathway

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