Dose-dependent effects of isoflurane on TrkB and GSK3β signaling: Importance of burst suppression pattern.

OBJECTIVES: Deep burst-suppressing isoflurane anesthesia regulates signaling pathways connected with antidepressant responses in the rodent brain: activation of TrkB neurotrophin receptor and inhibition of GSK3β kinase (glycogen synthase kinase 3β). The main objective of this study was to investigate whether EEG (electroencephalogram) burst suppression correlates with these intriguing molecular alterations induced by isoflurane.

METHODS: Adult male mice pre-implanted with EEG recording electrodes were subjected to varying concentrations of isoflurane (1.0-2.0% ad 20 min) after which medial prefrontal cortex samples were collected for molecular analyses, and the data retrospectively correlated to EEG (+/- burst suppression).

RESULTS: Isoflurane dose-dependently increased phosphorylation of TrkBY816 , CREBS133 (cAMP response element binding protein), GSK3βS9 and p70S6kT412/S424 . The time spent in burst suppression mode varied considerably between individual animals. Notably, a subset of animals subjected to 1.0-1.5% isoflurane showed no burst suppression. While p-GSK3βS9 , p-CREBS133 and p-p70S6kT412/S424 levels were increased in the samples obtained also from these animals, p-TrkBY816 levels remained unaltered.

CONCLUSIONS: Isoflurane dose-dependently regulates TrkB and GSK3β signaling and dosing associated with therapeutic outcomes in depressed patients produces most prominent effects.