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Early Isoflurane Exposure Impairs Synaptic Development in Fmr1 KO Mice via the mTOR Pathway

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Abstract

General anesthetics (GAs) may cause disruptions in brain development, and the effect of GA exposure in the setting of pre-existing neurodevelopmental disease is unknown. We tested the hypothesis that synaptic development is more vulnerable to GA-induced deficits in a mouse model of fragile X syndrome than in WT mice and asked whether they were related to the mTOR pathway, a signaling system implicated in both anesthesia toxicity and fragile X syndrome. Early postnatal WT and Fmr1-KO mice were exposed to isoflurane and brain slices were collected in adulthood. Primary neuron cultures isolated from WT and Fmr1-KO mice were exposed to isoflurane during development, in some cases treated with rapamycin, and processed for immunohistochemistry at maturity. Quantitative immunofluorescence microscopy was conducted for synaptic markers and markers of mTOR pathway activity. Isoflurane exposure caused reduction in Synpasin-1, PSD-95, and Gephyrin puncta that was significantly lower in Fmr1-KO mice than in WT mice. Similar results were found in cell culture, where synapse loss was ameliorated with rapamycin treatment. Early developmental exposure to isoflurane causes more profound synapse loss in Fmr1- KO than WT mice, and this effect is mediated by a pathologic increase in mTOR pathway activity.

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Data Availability

The datasets are available from the corresponding author upon reasonable request.

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Acknowledgements

This study is supported in part by the Chinese Scholarship Council (Second Affiliated Hospital of Xi'an Jiaotong University) and the NIH (Johns Hopkins University School of Medicine—Grant Nos. R01GM137213 and R01GM120519).

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Authors and Affiliations

  1. Department of Anesthesiology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, China

    Jieqiong Wen

  2. Department of Anesthesiology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, China

    Jing Xu

  3. Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Jieqiong Wen, Jing Xu, R. Paige Mathena, Jun H. Choi & C. David Mintz

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  1. Jieqiong Wen
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  2. Jing Xu
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  3. R. Paige Mathena
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  4. Jun H. Choi
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  5. C. David Mintz
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Contributions

Data curation: JW and JX; formal analysis: JW and JHC; funding acquisition: JW and CDM; methodology: JW, JX, RPM, JHC, and CDM; software: JW; supervision: CDM; writing—original draft: JW, JX, and CDM; Writing—review and editing: JX, RPM, and CDM All authors reviewed the final manuscript.

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Correspondence to C. David Mintz.

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Wen, J., Xu, J., Mathena, R.P. et al. Early Isoflurane Exposure Impairs Synaptic Development in Fmr1 KO Mice via the mTOR Pathway. Neurochem Res 46, 1577–1588 (2021). https://doi.org/10.1007/s11064-021-03301-5

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