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 journalArticlepeer-review


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 languageEnglish
Article number186
JournalTranslational Psychiatry
Issue number1
StatePublished - 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


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