General anesthesia-associated cognition impairment has been becoming one of the major issues derived from medical procedure, particularly when it was performed in younger patients. Our previous data noted that early exposure of sevoflurane impaired the adulthood spatial memory function in dose and time-dependent manner. Gamma aminobutyric acid (GABA) is the key inhibitory neurotransmitter in the central nervous system, and functions through mediating Wnt signaling pathway. The pontine GABA takes a special part in keeping awakening. We in this study investigated the role of pontine GABA signaling pathway activation in sevoflurane anesthesia-related long-term cognition in infantile rats via intracranial microinjection of CaMKII inhibitor KN-93 into the pons under different minimum alveolar concentrations of seveflurane. Morris Water Maze (MWM) was used to detect the spatial memory changes after speculated interventions. The results showed that pontile inhibition of GABA-Wnt-CaMKII through blocking CaMKII substantially alleviated sevoflurane-induced long-term special memory, which demonstrated dose- and time-dependent association. These preliminary observations indicated that the pontile GABA signaling plays an essential role in sevoflurane-induced adulthood cognition impairment, and further evaluation is needed on the exact interaction among sevoflurane, GABA, glutamate, receptors, corresponding signaling mediators, and cognition alteration in the pontine region.
Sevoflurane, Cognition, Pons, GABA, Wnt, CaMKII
2. Ing C, DiMaggio C, Whitehouse A, Hegarty MK, Brady J, von Ungern-Sternberg BS, Davidson A, Wood AJ, Li G, Sun LS. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics 2012; 130: e476-e485.
3. Wang X, Xu Z, Miao CH. Current clinical evidence on the effect of general anesthesia on neurodevelopment in children: an updated systematic review with meta-regression. PLoS One 2014; 9: e85760.
4. Olsen EA, Brambrink AM. Anesthesia for the young child undergoing ambulatory procedures: current concerns regarding harm to the developing brain. Curr Opin Anaesthesiol 2013; 26: 677-684.
5. Sinner B, Becke K, Engelhard K. Neurotoxicity of general anesthetics in childhood: does anesthesia leave its mark on premature babies, newborns and infants? Anaesthesist 2013; 62: 91-100.
6. Zheng SQ, An LX, Cheng X, Wang YJ. Sevoflurane causes neuronal apoptosis and adaptability changes of neonatal rats. Acta Anaesthesiol Scand 2013; 57: 1167-1174.
7. Rivera-Cruz B. Mitochondrial diseases and anesthesia: a literature review of current opinions. AANA J 2013; 81: 237-243.
8. Xiong WX, Zhou GX, Wang B, Xue ZG, Wang L, Sun HC, Ge SJ. Impaired spatial learning and memory after sevoflurane–nitrous oxide anesthesia in aged rats is associated with down-regulated cAMP/CREB signaling. PLoS One 2013; 8: e79408.
9. Le Freche H, Brouillette J, Fernandez-Gomez FJ, Patin P, Caillierez R, Zommer N, Sergeant N, Buée-Scherrer V, Lebuffe G, Blum D, Buée L. Tau phosphorylation and sevoflurane anesthesia: an association to postoperative cognitive impairment. Anesthesiology 2012; 116: 779-787.
10. Platholi J, Herold KF, Hemmings HC Jr, Halpain S. Isoflurane reversibly destabilizes hippocampal dendritic spines by an actin-dependent mechanism. PLoS One 2014; 9: e102978.
11. Hudson AE, Hemmings HC Jr. Are anaesthetics toxic to the brain? Br J Anaesth 2011; 107: 30-37.
12. Buffington SA, Huang W, Costa-Mattioli M. Translational control in synaptic plasticity and cognitive dysfunction. Annu Rev Neurosci 2014; 37: 17-38.
13. Shen X, Liu Y, Xu S, Zhao Q, Guo X, Shen R, Wang F. Early life exposure to sevoflurane impairs adulthood spatial memory in the rat. NeuroToxicology 2013; 39: 45-56.
14. Lecker I, Yin Y, Wang DS, Orser BA. Potentiation of GABAA receptor activity by volatile anaesthetics is reduced by alpha5GABAA receptor-preferring inverse agonists. Br J Anaesth 2013; 110: i73-i81.
15. Kotani N, Akaike N. The effects of volatile anesthetics on synaptic and extrasynaptic GABA-induced neurotransmission. Brain Res Bull 2013; 93: 69-79.
16. Sandiego CM, Jin X, Mulnix T, Fowles K, Labaree D, Ropchan J, Huang Y, Cosgrove K, Castner SA, Williams GV, Wells L, Rabiner EA, Carson RE. Awake nonhuman primate brain PET imaging with minimal head restraint: evaluation of GABAA-benzodiazepine binding with 11C-flumazenil in awake and anesthetized animals. J Nucl Med 2013; 54: 1962-1968.
17. Wu B, Yu Z, You S, Zheng Y, Liu J, Gao Y, Lin H, Lian Q. Physiological disturbance may contribute to neurodegeneration induced by isoflurane or sevoflurane in 14 day old rats. PLoS One 2014; 9: e84622.
18. Wisniewska MB, Nagalski A, Dabrowski M, Misztal K, Kuznicki J. Novel beta-catenin target genes identified in thalamic neurons encode modulators of neuronal excitability. BMC Genomics 2012; 13: 635.
19. Sandberg DI, Edgar MA, Souweidane MM. Convection-enhanced delivery into the rat brainstem. J Neurosurg 2002; 96: 885-891.
20. Dickins EM, Salinas PC. Wnts in action: from synapse formation to synaptic maintenance. Front Cell Neurosci 2013; 7: 162.
21. Fagotto F. Looking beyond the Wnt pathway for the deep nature of beta-catenin. EMBO Rep 2013; 14: 422-433.
22. Bemben MA, Shipman SL, Hirai T, Herring BE, Li Y, Badger JD 2nd, Nicoll RA, Diamond JS, Roche KW. CaMKII phosphorylation of neuroligin-1 regulates excitatory synapses. Nat Neurosci 2014; 17: 56-64.
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