Increased Notch2/NF-κB Signaling May Mediate the Depression Susceptibility: Evidence from Chronic Social Defeat Stress Mice and WKY Rats

Highlights

• The Wistar Kyoto rats may be separated into the depression and non-depression subgroups.

• Mice exposed to chronic social defeat stress can be divided into the susceptible and resilient subgroups.

• Increased Notch2/NF-κB signaling in the medial prefrontal cortex correlates with the depression susceptibility.

• Increased Notch2/NF-κB signaling may provide a potential diagnostic biomarker or therapeutic target for major depressive disorder.

Abstract

The susceptibility to depression has been attributed to the chronic stress and genetic factors but still fails to identify definite biomarkers. The present study aimed to investigate the role of disrupted Notch signaling in the medial prefrontal cortex of the chronic social defeat stress (CSDS) mice and Wistar Kyoto (WKY) rats. RNA-sequencing and quantitative real-time PCR analyses evidenced the involvement of Notch signaling pathway in depression. Western blotting reported an increased level of Notch2 and NF-κB and a decreased level of Hes1 and Bcl2/Bax ratio both in the susceptible mice when compared with the control or resilient ones and in the depression WKY rats when compared with the Wistar or non-depression WKY groups. Further analysis showed that the above-mentioned changes were significantly correlated with the depression-like behaviors and that the elicited Notch2 strongly correlated with the upregulated NF-κB, not with the downregulated Hes1 or Bcl2/Bax ratio. In conclusion, the increased Notch2/NF-κB signaling in the medial prefrontal cortex may mediate depression susceptibility, providing a potential diagnostic biomarker or therapeutic target for treating major depressive disorder.

Introduction

Major depressive disorder (MDD), as a common severe psychiatric condition, can be triggered by genetic and environmental factors and has a lifetime prevalence of about 16.6% in adults [1] and results in the highest disability burden among all mental and behavioral disorders [2]. It is characterized by mood despondency, disinterest, loss of concentration, and increased propensity for suicidal thoughts [3]. Worse still, the current diagnosis of MDD is often challenged by a lack of sensitive and specific biomarkers and the efficacy of the treatment strategies is often compromised due to the delayed symptomatic improvement, uncertain therapeutic value, and side effects of the used drugs [4]. Therefore, it is crucial to understand the mechanisms underpinning the depression occurrence so as to identify novel therapeutic targets.

In the pathogenesis of depression, the medial prefrontal cortex (mPFC) is closely related with the physiological and behavioral responses to stress. A large body of evidence demonstrates that chronic stress may affect both the structure and function of the mPFC [4], [5], [6]. However, the molecular adaptions in the mPFC underlying stress-induced depression-like behaviors remain to be further elucidated.

In the central nervous system (CNS), canonical Notch signaling pathway, a highly-conserved cell signaling system, participates in numerous pathophysiological processes, including cell differentiation, neurogenesis and apoptosis, inflammation, as well as synaptic plasticity [7, 8]. It is composed of four single-pass transmembrane Notch receptor genes (Notch1-4), five DSL (Delta, Serrate, Lag2) ligand genes (Jagged, Jag-1 and -2; Delta-like, Dll-1, -3, and -4), and multiple downstream target genes in mammals, including the nuclear factor-kB (NF-kB) [7]. In the occurrence of depression, NF-kB plays an important role via neurogenesis, neuroinflammation, synaptic transmission and plasticity [9, 10]. However, the role of Notch signaling pathway in depression has been controversial. Clinical studies have found increased Notch-associated microRNA levels and reduced Notch1 gene expression in the peripheral blood of MDD patients [11], and increased Notch2 level in plasma of patients with Parkinson's disease-related depression (PDD) [12]. In animal models of depression, although the expression of Notch1 has been found to decrease in the hippocampus of chronic unpredictable mild stress (CUMS) mice [13] and post-stroke depression (PSD) rats [14], studies also indicated an increase of Notch1 in the dentate gyrus of PSD rats [15]. Recent studies show that nicotine or silence/inhibition of miR-9 can activate the Notch signaling in the hippocampus and ameliorate the depressive symptoms of mice [13, 16, 17], while others report that therapeutic inhibition of gamma secretase-mediated Notch signaling activation can alleviate the PSD symptoms [15]. Still other studies suggest that the role of activated hippocampal Notch signaling pathway fluctuated in the proliferation and differentiation of progenitor cells in PSD [14, 18]. Taken together, the inconsistencies suggest that more efforts are still awaited to unravel the unresolved paradox and shed light on the relationship between the Notch signaling pathway and MDD occurrence.

The present study aimed to investigate the alteration of Notch signaling pathway in the mPFC and its role in MDD with two animal models, the chronic social defeat stress (CSDS) mice and the Wistar Kyoto (WKY) rats with endogenous depression [19, 20]. We compared the depression-like behaviors and the Notch signaling-related molecules of the vulnerable and resilient animals in the two models. We evidenced that increased Notch2/NF-κB signaling in the mPFC of both animal models may promote the depression occurrence, which provides a potential diagnostic biomarker or therapeutic target for MDD treatment.