Genetic inactivation of mTORC1 or mTORC2 in neurons reveals distinct functions in glutamatergic synaptic transmission
- University of Vermont, United States
Abstract
Although mTOR signaling is known as a broad regulator of cell growth and proliferation, in neurons it regulates synaptic transmission, which is thought to be a major mechanism through which altered mTOR signaling leads to neurological disease. Although previous studies have delineated postsynaptic roles for mTOR, whether it regulates presynaptic function is largely unknown. Moreover, the mTOR kinase operates in two complexes, mTORC1 and mTORC2, suggesting that mTOR's role in synaptic transmission may be complex-specific. To better understand their roles in synaptic transmission, we genetically inactivated mTORC1 or mTORC2 in cultured mouse glutamatergic hippocampal neurons. Inactivation of either complex reduced neuron growth and evoked EPSCs (eEPSCs), however, the effects of mTORC1 on eEPSCs were postsynaptic and the effects of mTORC2 were presynaptic. Despite postsynaptic inhibition of evoked release, mTORC1 inactivation enhanced spontaneous vesicle fusion and replenishment, suggesting that mTORC1 and mTORC2 differentially modulate postsynaptic responsiveness and presynaptic release to optimize glutamatergic synaptic transmission.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Caitlynn M Barrows
Funding
National Institute of Neurological Disorders and Stroke (R00NS087095)
- Matthew C Weston
National Institute of Neurological Disorders and Stroke (R01NS110945)
- Matthew C Weston
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the University of Vermont. The protocol was approved by the University of Vermont's Research Protections Office (Protocol Number: 16-001). All animals were killed under isofluorane anesthesia, and every effort was made to minimize suffering.
Copyright
© 2020, McCabe et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Genetic inactivation of mTORC1 or mTORC2 in neurons reveals distinct functions in glutamatergic synaptic transmission
eLife 9:e51440.
https://doi.org/10.7554/eLife.51440
