A role for BDNF- and NMDAR-induced lysosomal recruitment of mTORC1 in the regulation of neuronal mTORC1 activity
Abstract Memory and long term potentiation require de novo protein synthesis. A key regulator of this process is mTORC1, a complex comprising the mTOR kinase. Growth factors activate mTORC1 via a pathway involving PI3-kinase, Akt, the TSC complex and the GTPase Rheb. In non-neuronal cells, transloca...
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| Format: | Article |
| Language: | English |
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BMC
2021-07-01
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| Series: | Molecular Brain |
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| Online Access: | https://doi.org/10.1186/s13041-021-00820-8 |
| _version_ | 1818922543256436736 |
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| author | Dany Khamsing Solène Lebrun Isabelle Fanget Nathanaël Larochette Christophe Tourain Vincent de Sars Maia Brunstein Martin Oheim Damien Carrel François Darchen Claire Desnos |
| author_facet | Dany Khamsing Solène Lebrun Isabelle Fanget Nathanaël Larochette Christophe Tourain Vincent de Sars Maia Brunstein Martin Oheim Damien Carrel François Darchen Claire Desnos |
| author_sort | Dany Khamsing |
| collection | DOAJ |
| description | Abstract Memory and long term potentiation require de novo protein synthesis. A key regulator of this process is mTORC1, a complex comprising the mTOR kinase. Growth factors activate mTORC1 via a pathway involving PI3-kinase, Akt, the TSC complex and the GTPase Rheb. In non-neuronal cells, translocation of mTORC1 to late endocytic compartments (LEs), where Rheb is enriched, is triggered by amino acids. However, the regulation of mTORC1 in neurons remains unclear. In mouse hippocampal neurons, we observed that BDNF and treatments activating NMDA receptors trigger a robust increase in mTORC1 activity. NMDA receptors activation induced a significant recruitment of mTOR onto lysosomes even in the absence of external amino acids, whereas mTORC1 was evenly distributed in neurons under resting conditions. NMDA receptor-induced mTOR translocation to LEs was partly dependent on the BDNF receptor TrkB, suggesting that BDNF contributes to the effect of NMDA receptors on mTORC1 translocation. In addition, the combination of Rheb overexpression and artificial mTORC1 targeting to LEs by means of a modified component of mTORC1 fused with a LE-targeting motif strongly activated mTOR. To gain spatial and temporal control over mTOR localization, we designed an optogenetic module based on light-sensitive dimerizers able to recruit mTOR on LEs. In cells expressing this optogenetic tool, mTOR was translocated to LEs upon photoactivation. In the absence of growth factor, this was not sufficient to activate mTORC1. In contrast, mTORC1 was potently activated by a combination of BDNF and photoactivation. The data demonstrate that two important triggers of synaptic plasticity, BDNF and NMDA receptors, synergistically power the two arms of the mTORC1 activation mechanism, i.e., mTORC1 translocation to LEs and Rheb activation. Moreover, they unmask a functional link between NMDA receptors and mTORC1 that could underlie the changes in the synaptic proteome associated with long-lasting changes in synaptic strength. |
| first_indexed | 2024-12-20T01:55:13Z |
| format | Article |
| id | doaj.art-a30ef15727c446659a971dac33634341 |
| institution | Directory Open Access Journal |
| issn | 1756-6606 |
| language | English |
| last_indexed | 2024-12-20T01:55:13Z |
| publishDate | 2021-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Brain |
| spelling | doaj.art-a30ef15727c446659a971dac336343412022-12-21T19:57:30ZengBMCMolecular Brain1756-66062021-07-0114112010.1186/s13041-021-00820-8A role for BDNF- and NMDAR-induced lysosomal recruitment of mTORC1 in the regulation of neuronal mTORC1 activityDany Khamsing0Solène Lebrun1Isabelle Fanget2Nathanaël Larochette3Christophe Tourain4Vincent de Sars5Maia Brunstein6Martin Oheim7Damien Carrel8François Darchen9Claire Desnos10Saints-Pères Paris Institute for the Neurosciences, Université de Paris, Centre National de la Recherche Scientifique UMR 8003Saints-Pères Paris Institute for the Neurosciences, Université de Paris, Centre National de la Recherche Scientifique UMR 8003Saints-Pères Paris Institute for the Neurosciences, Université de Paris, Centre National de la Recherche Scientifique UMR 8003Saints-Pères Paris Institute for the Neurosciences, Université de Paris, Centre National de la Recherche Scientifique UMR 8003Wavefront-Engineering Microscopy Group, Sorbonne Université, INSERM S968, CNRS UMR7210, Institut de la VisionWavefront-Engineering Microscopy Group, Sorbonne Université, INSERM S968, CNRS UMR7210, Institut de la VisionSaints-Pères Paris Institute for the Neurosciences, Université de Paris, Centre National de la Recherche Scientifique UMR 8003Saints-Pères Paris Institute for the Neurosciences, Université de Paris, Centre National de la Recherche Scientifique UMR 8003Saints-Pères Paris Institute for the Neurosciences, Université de Paris, Centre National de la Recherche Scientifique UMR 8003Saints-Pères Paris Institute for the Neurosciences, Université de Paris, Centre National de la Recherche Scientifique UMR 8003Saints-Pères Paris Institute for the Neurosciences, Université de Paris, Centre National de la Recherche Scientifique UMR 8003Abstract Memory and long term potentiation require de novo protein synthesis. A key regulator of this process is mTORC1, a complex comprising the mTOR kinase. Growth factors activate mTORC1 via a pathway involving PI3-kinase, Akt, the TSC complex and the GTPase Rheb. In non-neuronal cells, translocation of mTORC1 to late endocytic compartments (LEs), where Rheb is enriched, is triggered by amino acids. However, the regulation of mTORC1 in neurons remains unclear. In mouse hippocampal neurons, we observed that BDNF and treatments activating NMDA receptors trigger a robust increase in mTORC1 activity. NMDA receptors activation induced a significant recruitment of mTOR onto lysosomes even in the absence of external amino acids, whereas mTORC1 was evenly distributed in neurons under resting conditions. NMDA receptor-induced mTOR translocation to LEs was partly dependent on the BDNF receptor TrkB, suggesting that BDNF contributes to the effect of NMDA receptors on mTORC1 translocation. In addition, the combination of Rheb overexpression and artificial mTORC1 targeting to LEs by means of a modified component of mTORC1 fused with a LE-targeting motif strongly activated mTOR. To gain spatial and temporal control over mTOR localization, we designed an optogenetic module based on light-sensitive dimerizers able to recruit mTOR on LEs. In cells expressing this optogenetic tool, mTOR was translocated to LEs upon photoactivation. In the absence of growth factor, this was not sufficient to activate mTORC1. In contrast, mTORC1 was potently activated by a combination of BDNF and photoactivation. The data demonstrate that two important triggers of synaptic plasticity, BDNF and NMDA receptors, synergistically power the two arms of the mTORC1 activation mechanism, i.e., mTORC1 translocation to LEs and Rheb activation. Moreover, they unmask a functional link between NMDA receptors and mTORC1 that could underlie the changes in the synaptic proteome associated with long-lasting changes in synaptic strength.https://doi.org/10.1186/s13041-021-00820-8mTOREndo-lysosomesNMDA receptorsBDNFSynaptic plasticityOptogenetics |
| spellingShingle | Dany Khamsing Solène Lebrun Isabelle Fanget Nathanaël Larochette Christophe Tourain Vincent de Sars Maia Brunstein Martin Oheim Damien Carrel François Darchen Claire Desnos A role for BDNF- and NMDAR-induced lysosomal recruitment of mTORC1 in the regulation of neuronal mTORC1 activity Molecular Brain mTOR Endo-lysosomes NMDA receptors BDNF Synaptic plasticity Optogenetics |
| title | A role for BDNF- and NMDAR-induced lysosomal recruitment of mTORC1 in the regulation of neuronal mTORC1 activity |
| title_full | A role for BDNF- and NMDAR-induced lysosomal recruitment of mTORC1 in the regulation of neuronal mTORC1 activity |
| title_fullStr | A role for BDNF- and NMDAR-induced lysosomal recruitment of mTORC1 in the regulation of neuronal mTORC1 activity |
| title_full_unstemmed | A role for BDNF- and NMDAR-induced lysosomal recruitment of mTORC1 in the regulation of neuronal mTORC1 activity |
| title_short | A role for BDNF- and NMDAR-induced lysosomal recruitment of mTORC1 in the regulation of neuronal mTORC1 activity |
| title_sort | role for bdnf and nmdar induced lysosomal recruitment of mtorc1 in the regulation of neuronal mtorc1 activity |
| topic | mTOR Endo-lysosomes NMDA receptors BDNF Synaptic plasticity Optogenetics |
| url | https://doi.org/10.1186/s13041-021-00820-8 |
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