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PLoS Biol. 2017 Jul 6;15(7):e2001246. doi: 10.1371/journal.pbio.2001246. eCollection 2017 Jul.

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

Author information

1
Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
2
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
3
Department of Anesthesiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
4
The Solomon Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

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.

PMID:
28683067
PMCID:
PMC5500005
DOI:
10.1371/journal.pbio.2001246
[Indexed for MEDLINE]
Free PMC Article

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