The Effect of Sevoflurane on Neuronal Degeneration and GABAA Subunit Composition in a Developing Rat Model of Organotypic Hippocampal Slice Cultures

Objective: The GABA(A) receptor subunit composition undergoes a switch from a predominantly alpha 2 to a predominantly alpha 1 around postnatal day (PND) 7 in a rat pup. This developmental switch in the GABA(A) receptor subunit composition changes the kinetics and pharmacologic properties of the GABA(A) receptor. Using a developmental organotypic hippocampal slice model, we hypothesized that the developmental changes in the GABA(A) receptor subunit composition may promote neurodegeneration after exposure to sevoflurane. Design: Organotypic hippocampal slices (OHS) were prepared from rat pups on PND 4, 7, and 14 and exposed to 2.0% sevoflurane or air for 5 hours. Hippocampal CA1, CA3, and dentate gyrus neuronal survival and GABA(A) receptor subunit composition were assessed immediately, 24 and 72 hours after exposure and compared with air. Measurements and Results: Early cell death immediately after exposure to sevoflurane was statistically significant in the PND14 (P < 0.001). At 24 hours, cell death was not significant for any PND age-examined OHS. However, at 72 hours, cell death was significant in the OHS prepared from the PND7 and 4 rat pups (P < 0.001). In further analysis, either a decrease in the a1 and/or increase in the alpha 2 subunit composition promoted cell survival in the PND 4 and 7 OHS. On PND14, cell survival was promoted by an increase in the alpha 1 subunit composition. Conclusions: This in vitro investigation supports an age-dependent and GABA(A) receptor subunit composition relationship between 2.0% sevoflurane exposure and cell death.