Comparative study of the effects of prenatal sevoflurane exposure at different cortical stages on forebrain development and maturation in offspring

Wang, Tianyuan; Weng, Huandi; Li, Yalan

doi:10.3389/fnins.2025.1556703

Title: Comparative study of the effects of prenatal sevoflurane exposure at different cortical stages on forebrain development and maturation in offspring

Journal Article · 03 April 2025 · Frontiers in Neuroscience (Online)

DOI: https://doi.org/10.3389/fnins.2025.1556703 · OSTI ID:2545947

Wang, Tianyuan; Weng, Huandi; Li, Yalan

Introduction Brain development involves several critical stages, such as proliferation, neuronal migration, axonal pathfinding, and connection formation. Sevoflurane, a γ -aminobutyric acid (GABA) receptor agonist, is widely used as an inhaled general anesthetic. However, its impact on brain development has raised increasing concerns, particularly regarding prenatal exposure. This study aims to investigate the effects of prenatal sevoflurane exposure (PSE) at different cortical stages, focusing on its impact on the migration of glutamatergic and GABAergic neurons and neuronal behavior in offspring. Methods PSE was administered at two critical prenatal stages: embryonic day (E) 12.5 and E18.5. Double in situ hybridization was used to identify the coexpression of GABA receptors in Pax6- and Mash1-positive cells in the forebrain. The radial migration of glutamatergic neurons and the tangential migration of GABAergic neurons were analyzed. Behavioral tests, including the open-field test, elevated plus-maze test, forced swim test, tail suspension test, sucrose preference test, and Morris water maze, were performed on offspring to assess anxiety-like behaviors, depression, and learning and memory impairments. Results PSE inhibits the radial migration of glutamatergic neurons and promotes the tangential migration of GABAergic neurons. Specifically, early exposure (E12.5) inhibited the expression of the Pax6–Tbr2–Tbr1 cascade and the radial migration of Tbr1 in the ventral prefrontal cortex (PFC), whereas late exposure (E18.5) inhibited this process on the dorsal side. In addition, offspring mice with PSE exhibited increased anxiety-like behaviors, rather than depression, as demonstrated by reduced time spent in the center of the open-field test and in the open arms of the elevated plus-maze test. No significant differences were observed in the forced swim test, tail suspension test, or sucrose preference test. Furthermore, learning and memory impairments were observed in the Morris water maze. Conclusion Our results indicate that PSE at E12.5 and E18.5 leads to abnormalities in the migration of glutamatergic and GABAergic neurons, affecting long-term anxiety-like behaviors and causing learning and memory impairments in offspring mice.

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Sponsoring Organization:: USDOE Office of Electricity (OE), Advanced Grid Research & Development. Power Systems Engineering Research

OSTI ID:: 2545947

Journal Information:: Frontiers in Neuroscience (Online), Journal Name: Frontiers in Neuroscience (Online) Vol. 19; ISSN 1662-453X

Publisher:: Frontiers Media SACopyright Statement

Country of Publication:: Switzerland

Language:: English

References (62)

Effects of prenatal alcohol exposure on the hippocampus: Spatial behavior, electrophysiology, and neuroanatomy Berman, Robert F.; Hannigan, John H. Hippocampus, Vol. 10, Issue 1 https://doi.org/10.1002/(SICI)1098-1063(2000)10:1<94::AID-HIPO11>3.0.CO;2-T	journal	January 2000
Anesthesia for Fetal Intervention and Surgery Olutoye, Olutoyin A.; Rosen, Mark; Rollins, Mark D. Gregory's Pediatric Anesthesia, Sixth Edition https://doi.org/10.1002/9781119371533.ch21	book	January 2020
Neurotransmitters and the Development of Neuronal Circuits Ruediger, Tina; Bolz, Juergen Axon Growth and Guidance https://doi.org/10.1007/978-0-387-76715-4_8	book	January 2007
Development of putative inhibitory neurons in the embryonic and postnatal mouse superficial spinal dorsal horn Balázs, Anita; Mészár, Zoltán; Hegedűs, Krisztina Brain Structure and Function, Vol. 222, Issue 5 https://doi.org/10.1007/s00429-016-1331-9	journal	October 2016
T-Brain-1: A homolog of Brachyury whose expression defines molecularly distinct domains within the cerebral cortex Bulfone, Alessandro; Smiga, Susan M.; Shimamura, Kenji Neuron, Vol. 15, Issue 1 https://doi.org/10.1016/0896-6273(95)90065-9	journal	July 1995
Advances in the molecular understanding of GABAB receptors Billinton, Andrew; Ige, Antoinette O.; Bolam, J. Paul Trends in Neurosciences, Vol. 24, Issue 5 https://doi.org/10.1016/S0166-2236(00)01815-4	journal	May 2001
Control of Neuronal Development by T-Box Genes in the Brain Mihalas, A. B.; Hevner, R. F. Current Topics in Developmental Biology https://doi.org/10.1016/bs.ctdb.2016.08.001	book	January 2017
Maternal sevoflurane exposure disrupts oligodendrocyte myelination of the postnatal hippocampus and induces cognitive and motor impairments in offspring Fan, Ze; Liang, Lirong; Ma, Ruixue Biochemical and Biophysical Research Communications, Vol. 614 https://doi.org/10.1016/j.bbrc.2022.05.037	journal	July 2022
Development and Evolution of the Human Neocortex Lui, Jan H.; Hansen, David V.; Kriegstein, Arnold R. Cell, Vol. 146, Issue 1 https://doi.org/10.1016/j.cell.2011.06.030	journal	July 2011
Growth of the Developing Cerebral Cortex Is Controlled by MicroRNA-7 through the p53 Pathway Pollock, Andrew; Bian, Shan; Zhang, Chao Cell Reports, Vol. 8, Issue 2 https://doi.org/10.1016/j.celrep.2014.07.009	journal	July 2014
Prenatal sevoflurane exposure causes neuronal excitatory/inhibitory imbalance in the prefrontal cortex and neurofunctional abnormality in rats Zhao, Tianyun; Chen, Yanxin; Sun, Zhixiang Neurobiology of Disease, Vol. 146 https://doi.org/10.1016/j.nbd.2020.105121	journal	December 2020
General anesthetic neurotoxicity in the young: Mechanism and prevention Ji, Chao; Ni, Qiang; Chen, Wurong Neuroscience & Biobehavioral Reviews, Vol. 107 https://doi.org/10.1016/j.neubiorev.2019.10.003	journal	December 2019
Sevoflurane anesthesia during pregnancy in mice induces cognitive impairment in the offspring by causing iron deficiency and inhibiting myelinogenesis Zuo, Yong; Li, Bowen; Xie, Jinhong Neurochemistry International, Vol. 135 https://doi.org/10.1016/j.neuint.2020.104693	journal	May 2020
Embryonic exposure to ethanol disturbs regulation of mitotic spindle orientation via GABAA receptors in neural progenitors in ventricular zone of developing neocortex Tochitani, Shiro; Sakata-Haga, Hiromi; Fukui, Yoshihiro Neuroscience Letters, Vol. 472, Issue 2 https://doi.org/10.1016/j.neulet.2010.01.071	journal	March 2010
Transcription factors in glutamatergic neurogenesis: Conserved programs in neocortex, cerebellum, and adult hippocampus Hevner, Robert F.; Hodge, Rebecca D.; Daza, Ray A. M. Neuroscience Research, Vol. 55, Issue 3 https://doi.org/10.1016/j.neures.2006.03.004	journal	July 2006
Maternal sevoflurane exposure affects neural stem cell differentiation in offspring rats through NRF2 signaling Zhang, Yinong; Kuai, Shihui; Zhang, Yi NeuroToxicology, Vol. 93 https://doi.org/10.1016/j.neuro.2022.10.014	journal	December 2022
Integration of GABAergic Interneurons into Cortical Cell Assemblies: Lessons from Embryos and Adults Bartolini, Giorgia; Ciceri, Gabriele; Marín, Oscar Neuron, Vol. 79, Issue 5 https://doi.org/10.1016/j.neuron.2013.08.014	journal	September 2013
GABAergic Interneurons in the Neocortex: From Cellular Properties to Circuits Tremblay, Robin; Lee, Soohyun; Rudy, Bernardo Neuron, Vol. 91, Issue 2 https://doi.org/10.1016/j.neuron.2016.06.033	journal	July 2016
Neonatal Tbr1 Dosage Controls Cortical Layer 6 Connectivity Fazel Darbandi, Siavash; Robinson Schwartz, Sarah E.; Qi, Qihao Neuron, Vol. 100, Issue 4 https://doi.org/10.1016/j.neuron.2018.09.027	journal	November 2018
Glutamate and GABA receptor signalling in the developing brain Luján, R.; Shigemoto, R.; López-Bendito, G. Neuroscience, Vol. 130, Issue 3 https://doi.org/10.1016/j.neuroscience.2004.09.042	journal	January 2005
The GABA excitatory/inhibitory developmental sequence: A personal journey Ben-Ari, Y. Neuroscience, Vol. 279 https://doi.org/10.1016/j.neuroscience.2014.08.001	journal	October 2014
GABAB receptors: modulation of thalamocortical dynamics and synaptic plasticity Sanchez-Vives, Maria V.; Barbero-Castillo, Almudena; Perez-Zabalza, Maria Neuroscience, Vol. 456 https://doi.org/10.1016/j.neuroscience.2020.03.011	journal	February 2021
Mid-gestational sevoflurane exposure inhibits fetal neural stem cell proliferation and impairs postnatal learning and memory function in a dose-dependent manner Wang, Yuan; Yin, Shaowei; Xue, Hang Developmental Biology, Vol. 435, Issue 2 https://doi.org/10.1016/j.ydbio.2018.01.022	journal	March 2018
Early fetal expression of GABAB1 and GABAB2 receptor mRNAs on the development of the rat central nervous system Kim, Myeong Ok; Li, Shupeng; Park, Moon Seok Developmental Brain Research, Vol. 143, Issue 1 https://doi.org/10.1016/s0165-3806(03)00099-3	journal	June 2003
Origin of GABAergic neurons in the human neocortex Letinic, Kresimir; Zoncu, Roberto; Rakic, Pasko Nature, Vol. 417, Issue 6889 https://doi.org/10.1038/nature00779	journal	June 2002
Shank3 mutant mice display autistic-like behaviours and striatal dysfunction Peça, João; Feliciano, Cátia; Ting, Jonathan T. Nature, Vol. 472, Issue 7344 https://doi.org/10.1038/nature09965	journal	March 2011
NKCC1 transporter facilitates seizures in the developing brain Dzhala, Volodymyr I.; Talos, Delia M.; Sdrulla, Dan A. Nature Medicine, Vol. 11, Issue 11 https://doi.org/10.1038/nm1301	journal	October 2005
Morris water maze: procedures for assessing spatial and related forms of learning and memory Vorhees, Charles V.; Williams, Michael T. Nature Protocols, Vol. 1, Issue 2 https://doi.org/10.1038/nprot.2006.116	journal	July 2006
Life is a journey: a genetic look at neocortical development Gupta, Amitabh; Tsai, Li-Huei; Wynshaw-Boris, Anthony Nature Reviews Genetics, Vol. 3, Issue 5 https://doi.org/10.1038/nrg799	journal	May 2002
Molecular logic of cellular diversification in the mouse cerebral cortex Di Bella, Daniela J.; Habibi, Ehsan; Stickels, Robert R. Nature, Vol. 595, Issue 7868 https://doi.org/10.1038/s41586-021-03670-5	journal	June 2021
Cell-type-resolved mosaicism reveals clonal dynamics of the human forebrain Chung, Changuk; Yang, Xiaoxu; Hevner, Robert F. Nature, Vol. 629, Issue 8011 https://doi.org/10.1038/s41586-024-07292-5	journal	April 2024
The differential effects of isoflurane and sevoflurane on neonatal mice Zhao, Shuai; Fan, Ziqi; Hu, Jing Scientific Reports, Vol. 10, Issue 1 https://doi.org/10.1038/s41598-020-76147-6	journal	November 2020
Low blood S-methyl-5-thioadenosine is associated with postoperative delayed neurocognitive recovery Zhang, Lei; Mao, Haoli; Zhou, Ren Communications Biology, Vol. 7, Issue 1 https://doi.org/10.1038/s42003-024-07086-5	journal	October 2024
Expression and distribution of metabotropic GABA receptor subtypes GABA_BR1 and GABA_BR2 during rat neocortical development López‐Bendito, G.; Shigemoto, R.; Kulik, A. European Journal of Neuroscience, Vol. 15, Issue 11 https://doi.org/10.1046/j.1460-9568.2002.02032.x	journal	June 2002
Embryonic exposure to environmental factors drives transmitter switching in the neonatal mouse cortex causing autistic-like adult behavior Godavarthi, Swetha K.; Li, Hui-quan; Pratelli, Marta Proceedings of the National Academy of Sciences, Vol. 121, Issue 35 https://doi.org/10.1073/pnas.2406928121	journal	August 2024
Measures for quantifying dendritic arborizations Uylings, Harry B. M.; van Pelt, Jaap Network: Computation in Neural Systems, Vol. 13, Issue 3 https://doi.org/10.1088/0954-898X_13_3_309	journal	January 2002
Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar Jevtovic-Todorovic, V.; Absalom, A. R.; Blomgren, K. British Journal of Anaesthesia, Vol. 111, Issue 2 https://doi.org/10.1093/bja/aet177	journal	August 2013
Blockade of GABAB Receptors Alters the Tangential Migration of Cortical Neurons Lopez-Bendito, G. Cerebral Cortex, Vol. 13, Issue 9 https://doi.org/10.1093/cercor/13.9.932	journal	September 2003
Ambient GABA Promotes Cortical Entry of Tangentially Migrating Cells Derived from the Medial Ganglionic Eminence Cuzon, Verginia C.; Yeh, Pamela W.; Cheng, Qing Cerebral Cortex, Vol. 16, Issue 10 https://doi.org/10.1093/cercor/bhj084	journal	December 2005
GABA-A Receptors Regulate Neocortical Neuronal Migration In Vitro and In Vivo Heck, N.; Kilb, W.; Reiprich, P. Cerebral Cortex, Vol. 17, Issue 1 https://doi.org/10.1093/cercor/bhj135	journal	February 2006
Altered Prefrontal Excitation/Inhibition Balance and Prefrontal Output: Markers of Aging in Human Memory Networks Legon, Wynn; Punzell, Steven; Dowlati, Ehsan Cerebral Cortex, Vol. 26, Issue 11 https://doi.org/10.1093/cercor/bhv200	journal	September 2015
Brain Maturation in Neonatal Rodents Is Impeded by Sevoflurane Anesthesia Makaryus, Rany; Lee, Hedok; Feng, Tian Anesthesiology, Vol. 123, Issue 3 https://doi.org/10.1097/ALN.0000000000000762	journal	September 2015
TBR1 regulates autism risk genes in the developing neocortex Notwell, James H.; Heavner, Whitney E.; Darbandi, Siavash Fazel Genome Research, Vol. 26, Issue 8 https://doi.org/10.1101/gr.203612.115	journal	June 2016
Maternal sevoflurane exposure induces temporary defects in interkinetic nuclear migration of radial glial progenitors in the fetal cerebral cortex through the Notch signalling pathway Jiang, Ming; Tang, Tianxiang; Liang, Xinyue Cell Proliferation, Vol. 54, Issue 6 https://doi.org/10.1111/cpr.13042	journal	May 2021
GABA Effects on Neurogenesis: An Arsenal of Regulation Yuan, Ti-Fei Science Signaling, Vol. 1, Issue 15 https://doi.org/10.1126/stke.115jc1	journal	April 2008
GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations Ben-Ari, Yehezkel; Gaiarsa, Jean-Luc; Tyzio, Roman Physiological Reviews, Vol. 87, Issue 4 https://doi.org/10.1152/physrev.00017.2006	journal	October 2007
Maternal Sevoflurane Exposure Causes Abnormal Development of Fetal Prefrontal Cortex and Induces Cognitive Dysfunction in Offspring Song, Ruixue; Ling, Xiaomin; Peng, Mengyuan Stem Cells International, Vol. 2017 https://doi.org/10.1155/2017/6158468	journal	January 2017
Maternal sevoflurane exposure increases the epilepsy susceptibility of adolescent offspring by interrupting interneuron development Liang, Xinyue; Jiang, Ming; Xu, Hao BMC Medicine, Vol. 21, Issue 1 https://doi.org/10.1186/s12916-023-03210-0	journal	December 2023
Prenatal Exposure to General Anesthesia and Childhood Behavioral Deficit Ing, Caleb; Landau, Ruth; DeStephano, David Anesthesia & Analgesia, Vol. 133, Issue 3 https://doi.org/10.1213/ANE.0000000000005389	journal	January 2021
Inhibitory control of the excitatory/inhibitory balance in psychiatric disorders Selten, Martijn; van Bokhoven, Hans; Nadif Kasri, Nael F1000Research, Vol. 7 https://doi.org/10.12688/f1000research.12155.1	journal	January 2018
The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development Laurie, Dj; Wisden, W.; Seeburg, Ph The Journal of Neuroscience, Vol. 12, Issue 11 https://doi.org/10.1523/JNEUROSCI.12-11-04151.1992	journal	November 1992
Persistent Interneuronopathy in the Prefrontal Cortex of Young Adult Offspring Exposed to Ethanol In Utero Skorput, A. G. J.; Gupta, V. P.; Yeh, P. W. L. Journal of Neuroscience, Vol. 35, Issue 31 https://doi.org/10.1523/JNEUROSCI.1462-15.2015	journal	August 2015
Excitatory GABA Responses in Embryonic and Neonatal Cortical Slices Demonstrated by Gramicidin Perforated-Patch Recordings and Calcium Imaging Owens, David F.; Boyce, Leslie H.; Davis, Marion B. E. The Journal of Neuroscience, Vol. 16, Issue 20 https://doi.org/10.1523/JNEUROSCI.16-20-06414.1996	journal	October 1996
Pax6, Tbr2, and Tbr1 Are Expressed Sequentially by Radial Glia, Intermediate Progenitor Cells, and Postmitotic Neurons in Developing Neocortex Englund, Chris; Fink, Andy; Lau, Charmaine The Journal of Neuroscience, Vol. 25, Issue 1 https://doi.org/10.1523/JNEUROSCI.2899-04.2005	journal	January 2005
Embryonically Expressed GABA and Glutamate Drive Electrical Activity Regulating Neurotransmitter Specification Root, Cory M.; Velázquez-Ulloa, Norma A.; Monsalve, Gabriela C. The Journal of Neuroscience, Vol. 28, Issue 18 https://doi.org/10.1523/JNEUROSCI.4873-07.2008	journal	April 2008
Ethanol Consumption during Early Pregnancy Alters the Disposition of Tangentially Migrating GABAergic Interneurons in the Fetal Cortex Cuzon, Verginia C.; Yeh, Pamela W. L.; Yanagawa, Yuchio The Journal of Neuroscience, Vol. 28, Issue 8 https://doi.org/10.1523/JNEUROSCI.5110-07.2008	journal	February 2008
Involvement of Netrins and Their Receptors in Neuronal Migration in the Cerebral Cortex Yamagishi, Satoru; Bando, Yuki; Sato, Kohji Frontiers in Cell and Developmental Biology, Vol. 8 https://doi.org/10.3389/fcell.2020.590009	journal	January 2021
Roles of taurine-mediated tonic GABAA receptor activation in the radial migration of neurons in the fetal mouse cerebral cortex Furukawa, Tomonori; Yamada, Junko; Akita, Tenpei Frontiers in Cellular Neuroscience, Vol. 8 https://doi.org/10.3389/fncel.2014.00088	journal	March 2014
Control of cortical neuronal migration by glutamate and GABA Luhmann, Heiko J.; Fukuda, A.; Kilb, W. Frontiers in Cellular Neuroscience, Vol. 9 https://doi.org/10.3389/fncel.2015.00004	journal	January 2015
The Structural E/I Balance Constrains the Early Development of Cortical Network Activity Xing, Wenxi; de Lima, Ana Dolabela; Voigt, Thomas Frontiers in Cellular Neuroscience, Vol. 15 https://doi.org/10.3389/fncel.2021.687306	journal	July 2021
PV Interneurons: Critical Regulators of E/I Balance for Prefrontal Cortex-Dependent Behavior and Psychiatric Disorders Ferguson, Brielle R.; Gao, Wen-Jun Frontiers in Neural Circuits, Vol. 12 https://doi.org/10.3389/fncir.2018.00037	journal	May 2018
Neonatal Anesthesia and Oxidative Stress Gascoigne, David A.; Minhaj, Mohammed M.; Aksenov, Daniil P. Antioxidants, Vol. 11, Issue 4 https://doi.org/10.3390/antiox11040787	journal	April 2022

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