Early postnatal exposure to isoflurane causes cognitive deficits and disrupts development of newborn hippocampal neurons via activation of the mTOR pathway

Eunchai Kang, Danye Jiang, Yun Kyoung Ryu, Sanghee Lim, Minhye Kwak, Christy D. Gray, Michael Xu, Jun H. Choi, Sue Junn, Jieun Kim, Jing Xu, Michele Schaefer, Roger A. Johns, Hongjun Song, Guo Li Ming, C. David Mintz*

*Corresponding author for this work

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Clinical and preclinical studies indicate that early postnatal exposure to anesthetics can lead to lasting deficits in learning and other cognitive processes. The mechanism underlying this phenomenon has not been clarified and there is no treatment currently available. Recent evidence suggests that anesthetics might cause persistent deficits in cognitive function by disrupting key events in brain development. The hippocampus, a brain region that is critical for learning and memory, contains a large number of neurons that develop in the early postnatal period, which are thus vulnerable to perturbation by anesthetic exposure. Using an in vivo mouse model we demonstrate abnormal development of dendrite arbors and dendritic spines in newly generated dentate gyrus granule cell neurons of the hippocampus after a clinically relevant isoflurane anesthesia exposure conducted at an early postnatal age. Furthermore, we find that isoflurane causes a sustained increase in activity in the mechanistic target of rapamycin pathway, and that inhibition of this pathway with rapamycin not only reverses the observed changes in neuronal development, but also substantially improves performance on behavioral tasks of spatial learning and memory that are impaired by isoflurane exposure. We conclude that isoflurane disrupts the development of hippocampal neurons generated in the early postnatal period by activating a well-defined neurodevelopmental disease pathway and that this phenotype can be reversed by pharmacologic inhibition.

Original languageEnglish
Article numbere2001246
Number of pages18
JournalPLoS Biology
Volume15
Issue number7
DOIs
Publication statusPublished - 6 Jul 2017

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    Kang, E., Jiang, D., Ryu, Y. K., Lim, S., Kwak, M., Gray, C. D., Xu, M., Choi, J. H., Junn, S., Kim, J., Xu, J., Schaefer, M., Johns, R. A., Song, H., Ming, G. L., & Mintz, C. D. (2017). Early postnatal exposure to isoflurane causes cognitive deficits and disrupts development of newborn hippocampal neurons via activation of the mTOR pathway. PLoS Biology, 15(7), [e2001246]. https://doi.org/10.1371/journal.pbio.2001246