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Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2

The mTOR pathway is an essential regulator of cell growth and metabolism. Midbrain dopamine neurons are particularly sensitive to mTOR signaling status as activation or inhibition of mTOR alters their morphology and physiology. mTOR exists in two distinct multiprotein complexes termed mTORC1 and mTO...

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Autores principales: Kosillo, Polina, Ahmed, Kamran M, Aisenberg, Erin E, Karalis, Vasiliki, Roberts, Bradley M, Cragg, Stephanie J, Bateup, Helen S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9328766/
https://www.ncbi.nlm.nih.gov/pubmed/35881440
http://dx.doi.org/10.7554/eLife.75398
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author Kosillo, Polina
Ahmed, Kamran M
Aisenberg, Erin E
Karalis, Vasiliki
Roberts, Bradley M
Cragg, Stephanie J
Bateup, Helen S
author_facet Kosillo, Polina
Ahmed, Kamran M
Aisenberg, Erin E
Karalis, Vasiliki
Roberts, Bradley M
Cragg, Stephanie J
Bateup, Helen S
author_sort Kosillo, Polina
collection PubMed
description The mTOR pathway is an essential regulator of cell growth and metabolism. Midbrain dopamine neurons are particularly sensitive to mTOR signaling status as activation or inhibition of mTOR alters their morphology and physiology. mTOR exists in two distinct multiprotein complexes termed mTORC1 and mTORC2. How each of these complexes affect dopamine neuron properties, and whether they have similar or distinct functions is unknown. Here, we investigated this in mice with dopamine neuron-specific deletion of Rptor or Rictor, which encode obligatory components of mTORC1 or mTORC2, respectively. We find that inhibition of mTORC1 strongly and broadly impacts dopamine neuron structure and function causing somatodendritic and axonal hypotrophy, increased intrinsic excitability, decreased dopamine production, and impaired dopamine release. In contrast, inhibition of mTORC2 has more subtle effects, with selective alterations to the output of ventral tegmental area dopamine neurons. Disruption of both mTOR complexes leads to pronounced deficits in dopamine release demonstrating the importance of balanced mTORC1 and mTORC2 signaling for dopaminergic function.
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spelling pubmed-93287662022-07-28 Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2 Kosillo, Polina Ahmed, Kamran M Aisenberg, Erin E Karalis, Vasiliki Roberts, Bradley M Cragg, Stephanie J Bateup, Helen S eLife Neuroscience The mTOR pathway is an essential regulator of cell growth and metabolism. Midbrain dopamine neurons are particularly sensitive to mTOR signaling status as activation or inhibition of mTOR alters their morphology and physiology. mTOR exists in two distinct multiprotein complexes termed mTORC1 and mTORC2. How each of these complexes affect dopamine neuron properties, and whether they have similar or distinct functions is unknown. Here, we investigated this in mice with dopamine neuron-specific deletion of Rptor or Rictor, which encode obligatory components of mTORC1 or mTORC2, respectively. We find that inhibition of mTORC1 strongly and broadly impacts dopamine neuron structure and function causing somatodendritic and axonal hypotrophy, increased intrinsic excitability, decreased dopamine production, and impaired dopamine release. In contrast, inhibition of mTORC2 has more subtle effects, with selective alterations to the output of ventral tegmental area dopamine neurons. Disruption of both mTOR complexes leads to pronounced deficits in dopamine release demonstrating the importance of balanced mTORC1 and mTORC2 signaling for dopaminergic function. eLife Sciences Publications, Ltd 2022-07-26 /pmc/articles/PMC9328766/ /pubmed/35881440 http://dx.doi.org/10.7554/eLife.75398 Text en © 2022, Kosillo, Ahmed et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
Kosillo, Polina
Ahmed, Kamran M
Aisenberg, Erin E
Karalis, Vasiliki
Roberts, Bradley M
Cragg, Stephanie J
Bateup, Helen S
Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2
title Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2
title_full Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2
title_fullStr Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2
title_full_unstemmed Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2
title_short Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2
title_sort dopamine neuron morphology and output are differentially controlled by mtorc1 and mtorc2
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9328766/
https://www.ncbi.nlm.nih.gov/pubmed/35881440
http://dx.doi.org/10.7554/eLife.75398
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