Early Isoflurane Exposure Impairs Synaptic Development in Fmr1 KO Mice via the mTOR Pathway
| Autor: | Jun H. Choi, C. David Mintz, R. Paige Mathena, Jing Xu, Jieqiong Wen |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Biochemistry Synapse 03 medical and health sciences Cellular and Molecular Neuroscience Fragile X Mental Retardation Protein 0302 clinical medicine Pregnancy Internal medicine medicine Animals PI3K/AKT/mTOR pathway Mice Knockout Neurons Sirolimus Gephyrin biology Isoflurane TOR Serine-Threonine Kinases Membrane Proteins General Medicine Synapsins FMR1 Mice Inbred C57BL 030104 developmental biology Endocrinology medicine.anatomical_structure Toxicity Anesthetics Inhalation Synapses biology.protein Immunohistochemistry Female Neuron Disks Large Homolog 4 Protein 030217 neurology & neurosurgery medicine.drug Signal Transduction |
| Zdroj: | Neurochemical research. 46(6) |
| ISSN: | 1573-6903 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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