Pten is a key intrinsic factor regulating raphe 5-HT neuronal plasticity and depressive behaviors in mice

Ling Chen; Wan Kun Gong; Cui ping Yang; Chan Chan Shao; Ning Ning Song; Jia Yin Chen; Li Qiang Zhou; Kun Shan Zhang; Siguang Li; Zhili Huang; Gal Richter-Levin; Lin Xu; Yu Qiang Ding

doi:10.1038/s41398-021-01303-z

Pten is a key intrinsic factor regulating raphe 5-HT neuronal plasticity and depressive behaviors in mice

Ling Chen, Wan Kun Gong, Cui ping Yang, Chan Chan Shao, Ning Ning Song, Jia Yin Chen, Li Qiang Zhou, Kun Shan Zhang, Siguang Li, Zhili Huang, Gal Richter-Levin, Lin Xu, Yu Qiang Ding

Research output: Contribution to journal › Article › peer-review

Abstract

Serotonin (5-HT)-based antidepressants, selective serotonin reuptake inhibitors (SSRIs) aim to enhance serotonergic activity by blocking its reuptake. We propose PTEN as a target for an alternative approach for regulating 5-HT neuron activity in the brain and depressive behaviors. We show that PTEN is elevated in central 5-HT neurons in the raphe nucleus by chronic stress in mice, and selective deletion of Pten in the 5-HT neurons induces its structural plasticity shown by increases of dendritic branching and density of PSD95-positive puncta in the dendrites. 5-HT levels are elevated and electrical stimulation of raphe neurons evokes more 5-HT release in the brain of condition knockout (cKO) mice with Pten-deficient 5-HT neurons. In addition, the 5-HT neurons remain normal electrophysiological properties but have increased excitatory synaptic inputs. Single-cell RNA sequencing revealed gene transcript alterations that may underlay morphological and functional changes in Pten-deficient 5-HT neurons. Finally, Pten cKO mice and wild-type mice treated with systemic application of PTEN inhibitor display reduced depression-like behaviors. Thus, PTEN is an intrinsic regulator of 5-HT neuron activity, representing a novel therapeutic strategy for producing antidepressant action.

Original language	English
Article number	186
Journal	Translational Psychiatry
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41398-021-01303-z
State	Published - 26 Mar 2021

Bibliographical note

Funding Information:
We thank Hanzhang Chris Ding for English Editing. This work was supported by grants from the National Natural Science Foundation of China (81200692 to L.C.; 81571332 to L.X., 81571332 and 91232724 to Y.-Q.D.), the National Key R&D Program of China (2017YFA0104002, to Y.-Q.D.), Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01 to N.-N.S and Y.-Q.D.), Shanghai Municipal Science and Technology Major Project (2018SHZDZX01) and ZJ Lab, and the Outstanding Clinical Discipline Project of Shanghai Pudong (PWYgy2018-10).

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Biological Psychiatry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41398-021-01303-z

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title = "Pten is a key intrinsic factor regulating raphe 5-HT neuronal plasticity and depressive behaviors in mice",

abstract = "Serotonin (5-HT)-based antidepressants, selective serotonin reuptake inhibitors (SSRIs) aim to enhance serotonergic activity by blocking its reuptake. We propose PTEN as a target for an alternative approach for regulating 5-HT neuron activity in the brain and depressive behaviors. We show that PTEN is elevated in central 5-HT neurons in the raphe nucleus by chronic stress in mice, and selective deletion of Pten in the 5-HT neurons induces its structural plasticity shown by increases of dendritic branching and density of PSD95-positive puncta in the dendrites. 5-HT levels are elevated and electrical stimulation of raphe neurons evokes more 5-HT release in the brain of condition knockout (cKO) mice with Pten-deficient 5-HT neurons. In addition, the 5-HT neurons remain normal electrophysiological properties but have increased excitatory synaptic inputs. Single-cell RNA sequencing revealed gene transcript alterations that may underlay morphological and functional changes in Pten-deficient 5-HT neurons. Finally, Pten cKO mice and wild-type mice treated with systemic application of PTEN inhibitor display reduced depression-like behaviors. Thus, PTEN is an intrinsic regulator of 5-HT neuron activity, representing a novel therapeutic strategy for producing antidepressant action.",

author = "Ling Chen and Gong, {Wan Kun} and Yang, {Cui ping} and Shao, {Chan Chan} and Song, {Ning Ning} and Chen, {Jia Yin} and Zhou, {Li Qiang} and Zhang, {Kun Shan} and Siguang Li and Zhili Huang and Gal Richter-Levin and Lin Xu and Ding, {Yu Qiang}",

note = "Funding Information: We thank Hanzhang Chris Ding for English Editing. This work was supported by grants from the National Natural Science Foundation of China (81200692 to L.C.; 81571332 to L.X., 81571332 and 91232724 to Y.-Q.D.), the National Key R&D Program of China (2017YFA0104002, to Y.-Q.D.), Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01 to N.-N.S and Y.-Q.D.), Shanghai Municipal Science and Technology Major Project (2018SHZDZX01) and ZJ Lab, and the Outstanding Clinical Discipline Project of Shanghai Pudong (PWYgy2018-10). Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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doi = "10.1038/s41398-021-01303-z",

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AU - Chen, Ling

AU - Gong, Wan Kun

AU - Yang, Cui ping

AU - Shao, Chan Chan

AU - Song, Ning Ning

AU - Chen, Jia Yin

AU - Zhou, Li Qiang

AU - Zhang, Kun Shan

AU - Li, Siguang

AU - Huang, Zhili

AU - Richter-Levin, Gal

AU - Xu, Lin

AU - Ding, Yu Qiang

N1 - Funding Information: We thank Hanzhang Chris Ding for English Editing. This work was supported by grants from the National Natural Science Foundation of China (81200692 to L.C.; 81571332 to L.X., 81571332 and 91232724 to Y.-Q.D.), the National Key R&D Program of China (2017YFA0104002, to Y.-Q.D.), Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01 to N.-N.S and Y.-Q.D.), Shanghai Municipal Science and Technology Major Project (2018SHZDZX01) and ZJ Lab, and the Outstanding Clinical Discipline Project of Shanghai Pudong (PWYgy2018-10). Publisher Copyright: © 2021, The Author(s).

PY - 2021/3/26

Y1 - 2021/3/26

N2 - Serotonin (5-HT)-based antidepressants, selective serotonin reuptake inhibitors (SSRIs) aim to enhance serotonergic activity by blocking its reuptake. We propose PTEN as a target for an alternative approach for regulating 5-HT neuron activity in the brain and depressive behaviors. We show that PTEN is elevated in central 5-HT neurons in the raphe nucleus by chronic stress in mice, and selective deletion of Pten in the 5-HT neurons induces its structural plasticity shown by increases of dendritic branching and density of PSD95-positive puncta in the dendrites. 5-HT levels are elevated and electrical stimulation of raphe neurons evokes more 5-HT release in the brain of condition knockout (cKO) mice with Pten-deficient 5-HT neurons. In addition, the 5-HT neurons remain normal electrophysiological properties but have increased excitatory synaptic inputs. Single-cell RNA sequencing revealed gene transcript alterations that may underlay morphological and functional changes in Pten-deficient 5-HT neurons. Finally, Pten cKO mice and wild-type mice treated with systemic application of PTEN inhibitor display reduced depression-like behaviors. Thus, PTEN is an intrinsic regulator of 5-HT neuron activity, representing a novel therapeutic strategy for producing antidepressant action.

AB - Serotonin (5-HT)-based antidepressants, selective serotonin reuptake inhibitors (SSRIs) aim to enhance serotonergic activity by blocking its reuptake. We propose PTEN as a target for an alternative approach for regulating 5-HT neuron activity in the brain and depressive behaviors. We show that PTEN is elevated in central 5-HT neurons in the raphe nucleus by chronic stress in mice, and selective deletion of Pten in the 5-HT neurons induces its structural plasticity shown by increases of dendritic branching and density of PSD95-positive puncta in the dendrites. 5-HT levels are elevated and electrical stimulation of raphe neurons evokes more 5-HT release in the brain of condition knockout (cKO) mice with Pten-deficient 5-HT neurons. In addition, the 5-HT neurons remain normal electrophysiological properties but have increased excitatory synaptic inputs. Single-cell RNA sequencing revealed gene transcript alterations that may underlay morphological and functional changes in Pten-deficient 5-HT neurons. Finally, Pten cKO mice and wild-type mice treated with systemic application of PTEN inhibitor display reduced depression-like behaviors. Thus, PTEN is an intrinsic regulator of 5-HT neuron activity, representing a novel therapeutic strategy for producing antidepressant action.

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DO - 10.1038/s41398-021-01303-z

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SN - 2158-3188

VL - 11

JO - Translational Psychiatry

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M1 - 186

ER -

Pten is a key intrinsic factor regulating raphe 5-HT neuronal plasticity and depressive behaviors in mice

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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