Cargando…

Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway

Human epidemiologic studies and laboratory investigations in animal models suggest that exposure to general anesthetic agents (GAs) have harmful effects on brain development. The mechanism underlying this putative iatrogenic condition is not clear and there are currently no accepted strategies for p...

Descripción completa

Detalles Bibliográficos
Autores principales: Xu, Jing, Mathena, R. Paige, Xu, Michael, Wang, YuChia, Chang, CheJui, Fang, Yiwen, Zhang, Pengbo, Mintz, C. David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121894/
https://www.ncbi.nlm.nih.gov/pubmed/30049952
http://dx.doi.org/10.3390/ijms19082183
_version_ 1783352557521862656
author Xu, Jing
Mathena, R. Paige
Xu, Michael
Wang, YuChia
Chang, CheJui
Fang, Yiwen
Zhang, Pengbo
Mintz, C. David
author_facet Xu, Jing
Mathena, R. Paige
Xu, Michael
Wang, YuChia
Chang, CheJui
Fang, Yiwen
Zhang, Pengbo
Mintz, C. David
author_sort Xu, Jing
collection PubMed
description Human epidemiologic studies and laboratory investigations in animal models suggest that exposure to general anesthetic agents (GAs) have harmful effects on brain development. The mechanism underlying this putative iatrogenic condition is not clear and there are currently no accepted strategies for prophylaxis or treatment. Recent evidence suggests that anesthetics might cause persistent deficits in synaptogenesis by disrupting key events in neurodevelopment. Using an in vitro model consisting of dissociated primary cultured mouse neurons, we demonstrate abnormal pre- and post-synaptic marker expression after a clinically-relevant isoflurane anesthesia exposure is conducted during neuron development. We find that pharmacologic inhibition of the mechanistic target of rapamycin (mTOR) pathway can reverse the observed changes. Isoflurane exposure increases expression of phospho-S6, a marker of mTOR pathway activity, in a concentration-dependent fashion and this effect occurs throughout neuronal development. The mTOR 1 complex (mTORC1) and the mTOR 2 complex (mTORC2) branches of the pathway are both activated by isoflurane exposure and this is reversible with branch-specific inhibitors. Upregulation of mTOR is also seen with sevoflurane and propofol exposure, suggesting that this mechanism of developmental anesthetic neurotoxicity may occur with all the commonly used GAs in pediatric practice. We conclude that GAs disrupt the development of neurons during development by activating a well-defined neurodevelopmental disease pathway and that this phenotype can be reversed by pharmacologic inhibition.
format Online
Article
Text
id pubmed-6121894
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-61218942018-09-07 Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway Xu, Jing Mathena, R. Paige Xu, Michael Wang, YuChia Chang, CheJui Fang, Yiwen Zhang, Pengbo Mintz, C. David Int J Mol Sci Article Human epidemiologic studies and laboratory investigations in animal models suggest that exposure to general anesthetic agents (GAs) have harmful effects on brain development. The mechanism underlying this putative iatrogenic condition is not clear and there are currently no accepted strategies for prophylaxis or treatment. Recent evidence suggests that anesthetics might cause persistent deficits in synaptogenesis by disrupting key events in neurodevelopment. Using an in vitro model consisting of dissociated primary cultured mouse neurons, we demonstrate abnormal pre- and post-synaptic marker expression after a clinically-relevant isoflurane anesthesia exposure is conducted during neuron development. We find that pharmacologic inhibition of the mechanistic target of rapamycin (mTOR) pathway can reverse the observed changes. Isoflurane exposure increases expression of phospho-S6, a marker of mTOR pathway activity, in a concentration-dependent fashion and this effect occurs throughout neuronal development. The mTOR 1 complex (mTORC1) and the mTOR 2 complex (mTORC2) branches of the pathway are both activated by isoflurane exposure and this is reversible with branch-specific inhibitors. Upregulation of mTOR is also seen with sevoflurane and propofol exposure, suggesting that this mechanism of developmental anesthetic neurotoxicity may occur with all the commonly used GAs in pediatric practice. We conclude that GAs disrupt the development of neurons during development by activating a well-defined neurodevelopmental disease pathway and that this phenotype can be reversed by pharmacologic inhibition. MDPI 2018-07-26 /pmc/articles/PMC6121894/ /pubmed/30049952 http://dx.doi.org/10.3390/ijms19082183 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Xu, Jing
Mathena, R. Paige
Xu, Michael
Wang, YuChia
Chang, CheJui
Fang, Yiwen
Zhang, Pengbo
Mintz, C. David
Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway
title Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway
title_full Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway
title_fullStr Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway
title_full_unstemmed Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway
title_short Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway
title_sort early developmental exposure to general anesthetic agents in primary neuron culture disrupts synapse formation via actions on the mtor pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121894/
https://www.ncbi.nlm.nih.gov/pubmed/30049952
http://dx.doi.org/10.3390/ijms19082183
work_keys_str_mv AT xujing earlydevelopmentalexposuretogeneralanestheticagentsinprimaryneuronculturedisruptssynapseformationviaactionsonthemtorpathway
AT mathenarpaige earlydevelopmentalexposuretogeneralanestheticagentsinprimaryneuronculturedisruptssynapseformationviaactionsonthemtorpathway
AT xumichael earlydevelopmentalexposuretogeneralanestheticagentsinprimaryneuronculturedisruptssynapseformationviaactionsonthemtorpathway
AT wangyuchia earlydevelopmentalexposuretogeneralanestheticagentsinprimaryneuronculturedisruptssynapseformationviaactionsonthemtorpathway
AT changchejui earlydevelopmentalexposuretogeneralanestheticagentsinprimaryneuronculturedisruptssynapseformationviaactionsonthemtorpathway
AT fangyiwen earlydevelopmentalexposuretogeneralanestheticagentsinprimaryneuronculturedisruptssynapseformationviaactionsonthemtorpathway
AT zhangpengbo earlydevelopmentalexposuretogeneralanestheticagentsinprimaryneuronculturedisruptssynapseformationviaactionsonthemtorpathway
AT mintzcdavid earlydevelopmentalexposuretogeneralanestheticagentsinprimaryneuronculturedisruptssynapseformationviaactionsonthemtorpathway