PTEN in prefrontal cortex is essential in regulating depression-like behaviors in mice

Xiao-Qing Wang,Yu-Qiang Ding,Zhong-Yuan Xia,Yiru Fang,Jia-Yin Chen,Lei Zhang

doi:10.1038/s41398-021-01312-y

Abstract

Chronic stress is an environmental risk factor for depression and causes neuronal atrophy in the prefrontal cortex (PFC) and other brain regions. It is still unclear about the molecular mechanism underlying the behavioral alterations and neuronal atrophy induced by chronic stress. We here report that phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a mediator for chronic stress-induced depression-like behaviors and neuronal atrophy in mice. One-month chronic restraint stress (CRS) up-regulated PTEN signaling pathway in the PFC of mice as indicated by increasing levels of PTEN, p-MEK, and p-ERK but decreasing levels of p-AKT. Over-expression of Pten in the PFC led to an increase of depression-like behaviors, whereas genetic inactivation or knockdown of Pten in the PFC prevented the CRS-induced depression-like behaviors. In addition, systemic administration of PTEN inhibitor was also able to prevent these behaviors. Cellular examination showed that Pten over-expression or the CRS treatment resulted in PFC neuron atrophy, and this atrophy was blocked by genetic inactivation of Pten or systemic administration of PTEN inhibitor. Furthermore, possible causal link between Pten and glucocorticoids was examined. In chronic dexamethasone (Dex, a glucocorticoid agonist) treatment-induced depression model, increased PTEN levels were observed, and depression-like behaviors and PFC neuron atrophy were attenuated by the administration of PTEN inhibitor. Our results indicate that PTEN serves as a key mediator in chronic stress-induced neuron atrophy as well as depression-like behaviors, providing molecular evidence supporting the synaptic plasticity theory of depression.

Highlights

Depression is a common and devastating illness, which leads to an elevated risk for suicide[1,2], as well as increased risks of cardiac disease, cerebrovascular disorders, and other medical causes of mortality[3]
We found that the PTEN levels were increased in the prefrontal cortex (PFC) of mice treated with chronic restraint stress (CRS) or chronic administration of dexamethasone (Dex), a synthetic glucocorticoid agonist
Sholl analysis showed that the cortical neurons lacking Pten had larger soma size (Fig. 4l, n, p) and increased dendrite length (Fig. 4l, n, q) and branches (Fig. 4l, n, r) compared with control mice. These alterations of Pten-deficient neurons were not observed in the mice with one-month CRS treatment (Fig. 4o–r). These results suggest that the inactivation of Pten in PFC neurons endows them with the ability against the CRS-induced neuronal atrophy, which may serve as one of the cellular mechanisms underlying the essential role of PTEN in regulating depression-like behaviors in mice

Summary

Introduction

Depression is a common and devastating illness, which leads to an elevated risk for suicide[1,2], as well as increased risks of cardiac disease, cerebrovascular disorders, and other medical causes of mortality[3]. PTEN is a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, and is involved in the brain development, axonal regeneration, and neurodegenerative diseases[16,17,18,19]. The elevated PTEN levels and lowered PI3K and Akt activities have been reported in the brain of depressed suicide victims[22,23], and overexpression of PTEN causes a reduction of dendrite complexity[24,25]. We hypothesized that PTEN may be involved in chronic stress-induced neuronal atrophy and depression-like behaviors

Methods

Results

Conclusion