Exposure to Sevoflurane, But Not Ketamine, During Early-life Brain Development has Long-Lasting Effects on GABAA Receptor Mediated Inhibitory Neurotransmission

• Published in: Neuroscience 2021-09, Vol.472, p.116-127
• Main Authors: Lin, Daisy, Liu, Jinyang, Florveus, Alizna, Ganesan, Vanathi, Cottrell, James E., Kass, Ira S.
• Format: Article
• Language: English
• Subjects: anxiety-like behavior; early-life anesthesia; GABA; ketamine; Seizures; sevoflurane
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2021.08.001

[Display omitted] •Sevoflurane mainly targets GABA receptors while ketamine targets NMDA receptors.•Early-life ketamine resulted in anxiety and depression-like behavior later in life.•Early-life sevoflurane, not ketamine, reduced hippocampal GABAergic inhibition.•Early-life sevoflurane, not ketamine, enhanced induced seizure activity later in life.•Anesthetic receptor targets may determine long-term effects after early-life treatment. Understanding the different mechanisms associated with different anesthetic targeted receptors is critical towards identifying accurate long-term outcome measures as a result of early-life anesthetic exposure. We examined changes in GABAA receptor mediated neurotransmission by a predominately GABAA receptor targeted anesthetic, sevoflurane or a predominately NMDA receptor targeted anesthetic, ketamine. Postnatal day 7 male mice were exposed to sevoflurane or ketamine and examined as adults for changes in inhibitory neurotransmission and its associated change in induced seizure activity. Paired pulse stimulation experiment showed that early-life sevoflurane treated mice had significantly less hippocampal CA1 inhibition later in life. There was significantly increased CA1 excitatory output in the sevoflurane treated group compared to the no sevoflurane treated group after the GABA agonist muscimol. Similar to our previously established data for early-life sevoflurane, here we established early-life ketamine administration resulted in neurodevelopmental behavioral changes later in life. However, muscimol did not produce a significant difference on the excitatory CA1 output between early-life ketamine group and saline group. While sevoflurane treated mice showed significantly higher induced seizure intensities and shorter latency periods to reach seizure intensity stage 5 (Racine score) compared with no sevoflurane treated mice, this phenomenon was not observed in the ketamine vs. saline treated groups. Early-life sevoflurane, but not ketamine, exposure reduced GABAergic inhibition and enhanced seizure activity later in life. The results indicate that early-life exposure to different anesthetics lead to distinct long-term effects and their unique pathways require mechanistic studies to understand induced long-lasting changes in the brain.