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

• Main Authors: 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
• Format: Article
• Language: English
• Published: Nature Publishing Group 2021-03-01
• Series: Translational Psychiatry
• Online Access: https://doi.org/10.1038/s41398-021-01303-z

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.