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Antipsychotics activate mTORC1-dependent translation to enhance neuronal morphological complexity

Antipsychotics activate mTORC1-dependent translation to enhance neuronal morphological complexity
Antipsychotics activate mTORC1-dependent translation to enhance neuronal morphological complexity
Although antipsychotic drugs can reduce psychotic behavior within a few hours, full efficacy is not achieved for several weeks, implying that there may be rapid, short-term changes in neuronal function, which are consolidated into long-lasting changes. We showed that the antipsychotic drug haloperidol, a dopamine receptor type 2 (D?R) antagonist, stimulated the kinase Akt to activate the mRNA translation pathway mediated by the mammalian target of rapamycin complex 1 (mTORC1). In primary striatal D?R-positive neurons, haloperidol-mediated activation of mTORC1 resulted in increased phosphorylation of ribosomal protein S6 (S6) and eukaryotic translation initiation factor 4E-binding protein (4E-BP). Proteomic mass spectrometry revealed marked changes in the pattern of protein synthesis after acute exposure of cultured striatal neurons to haloperidol, including increased abundance of cytoskeletal proteins and proteins associated with translation machinery. These proteomic changes coincided with increased morphological complexity of neurons that was diminished by inhibition of downstream effectors of mTORC1, suggesting that mTORC1-dependent translation enhances neuronal complexity in response to haloperidol. In vivo, we observed rapid morphological changes with a concomitant increase in the abundance of cytoskeletal proteins in cortical neurons of haloperidol-injected mice. These results suggest a mechanism for both the acute and long-term actions of antipsychotics
ra4
Bowling, Heather
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Zhang, Guoan
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Bhattacharya, Aditi
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Pérez-Cuesta, Luis M.
30558b1c-3b56-4732-a2ef-07370d80bd9c
Deinhardt, Katrin
5f4fe23b-2317-499f-ba6d-e639a4885dc1
Hoeffer, Charles A.
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Neubert, Thomas A.
bd2d3132-b85d-49fa-b879-488ac0e32ec7
Gan, Wen-biao
9c27cd9c-320d-45f7-af19-a720cef45c37
Klann, Eric
15afa55b-aaa0-4575-9a15-0844fe49f6fa
Chao, Moses V.
823c00e2-9f32-4a7b-a2c4-76e7c1fbf83d
Bowling, Heather
c9e586d5-af3f-4616-8975-ef503b3835df
Zhang, Guoan
fbb6a65f-dba6-43b8-aa9b-9a95f8c8a979
Bhattacharya, Aditi
d466aad7-4774-4291-a91f-b68b88c4f7f9
Pérez-Cuesta, Luis M.
30558b1c-3b56-4732-a2ef-07370d80bd9c
Deinhardt, Katrin
5f4fe23b-2317-499f-ba6d-e639a4885dc1
Hoeffer, Charles A.
30f87634-6bf9-48cc-9a83-cbdcc46d6e75
Neubert, Thomas A.
bd2d3132-b85d-49fa-b879-488ac0e32ec7
Gan, Wen-biao
9c27cd9c-320d-45f7-af19-a720cef45c37
Klann, Eric
15afa55b-aaa0-4575-9a15-0844fe49f6fa
Chao, Moses V.
823c00e2-9f32-4a7b-a2c4-76e7c1fbf83d

Bowling, Heather, Zhang, Guoan, Bhattacharya, Aditi, Pérez-Cuesta, Luis M., Deinhardt, Katrin, Hoeffer, Charles A., Neubert, Thomas A., Gan, Wen-biao, Klann, Eric and Chao, Moses V. (2014) Antipsychotics activate mTORC1-dependent translation to enhance neuronal morphological complexity. Science Signaling, 7 (308), ra4. (doi:10.1126/scisignal.2004331). (PMID:24425786)

Record type: Article

Abstract

Although antipsychotic drugs can reduce psychotic behavior within a few hours, full efficacy is not achieved for several weeks, implying that there may be rapid, short-term changes in neuronal function, which are consolidated into long-lasting changes. We showed that the antipsychotic drug haloperidol, a dopamine receptor type 2 (D?R) antagonist, stimulated the kinase Akt to activate the mRNA translation pathway mediated by the mammalian target of rapamycin complex 1 (mTORC1). In primary striatal D?R-positive neurons, haloperidol-mediated activation of mTORC1 resulted in increased phosphorylation of ribosomal protein S6 (S6) and eukaryotic translation initiation factor 4E-binding protein (4E-BP). Proteomic mass spectrometry revealed marked changes in the pattern of protein synthesis after acute exposure of cultured striatal neurons to haloperidol, including increased abundance of cytoskeletal proteins and proteins associated with translation machinery. These proteomic changes coincided with increased morphological complexity of neurons that was diminished by inhibition of downstream effectors of mTORC1, suggesting that mTORC1-dependent translation enhances neuronal complexity in response to haloperidol. In vivo, we observed rapid morphological changes with a concomitant increase in the abundance of cytoskeletal proteins in cortical neurons of haloperidol-injected mice. These results suggest a mechanism for both the acute and long-term actions of antipsychotics

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Accepted/In Press date: 2 December 2013
e-pub ahead of print date: 14 January 2014
Published date: 14 January 2014
Organisations: Centre for Biological Sciences

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Local EPrints ID: 362630
URI: http://eprints.soton.ac.uk/id/eprint/362630
PURE UUID: 1fb5d724-2682-4571-b415-d63e131532b0
ORCID for Katrin Deinhardt: ORCID iD orcid.org/0000-0002-6473-5298

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Date deposited: 03 Mar 2014 10:18
Last modified: 10 Dec 2019 01:36

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Contributors

Author: Heather Bowling
Author: Guoan Zhang
Author: Aditi Bhattacharya
Author: Luis M. Pérez-Cuesta
Author: Charles A. Hoeffer
Author: Thomas A. Neubert
Author: Wen-biao Gan
Author: Eric Klann
Author: Moses V. Chao

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