Major depressive disorder (MDD) is a major public health concern affecting 30 billion people worldwide (Deussing and Arzt, 2018). Symptoms such as a lack of pleasure, pessimism, and insomnia seriously affect and reduce the quality of life of patients with depression. As depression is a highly recurrent disease, its pathogenesis is complex (Fan et al., 2022). However, the current clinical use of antidepressants is associated with poor efficacy and side effects. Identifying key target proteins may improve depression treatment.

Neurogenesis is the most robust form of plasticity in the adult brain and may contribute to memory formation. In addition, adult-born neurons have been used to study neuronal development, and neurogenetic defects have been linked to several human neurological and psychiatric disorders (Gonçalves et al., 2016). Studies have shown that neurogenesis in humans and animals decreases with age, whereas the prevalence of depression increases with age (Knoth et al., 2010; Manganas et al., 2007; Eisch and Petrik, 2012). Patients with MDD may experience a reduction in hippocampal volume because of reduced neurogenesis (Malberg et al., 2000). Antidepressants promote neurogenesis, and the delay in the clinical effect of antidepressants may reflect the maturation time of adult hippocampal neurons (Eisch and Petrik, 2012). Since adult hippocampal neurons are required for emotional control and antidepressant efficacy, enhancing neurogenesis may be a method to treat emotional disorders, such as depression. However, the contradictory findings of preclinical studies (involving stress, depression, and neurogenesis) highlight the complexity of treating neurogenesis to relieve depression.

Ten-eleven translocation protein 1 (Tet1) belongs to the Tet translocation (Tet) family of methylcytosine dioxygenases, which also includes Tet2 and Tet3. Tet1 deficiency causes a decrease in the number of neural stem cells (NSCs) in the mouse hippocampus and poor learning and memory abilities, leading to neurological disorders (Zhang et al., 2013). Tet1 regulates the normal level of DNA methylation, expression of active regulatory genes, synaptic plasticity, and memory loss (Rudenko et al., 2013). DNA methylation is a covalent modification that plays an important role in development through its epigenetic effects (Jaenisch and Bird, 2003; Bergman and Cedar, 2013). DNA methylation involves transfer of a methyl group to cytosine to create 5-methylcytosine (5 mC). Once established, 5 mC is propagated by DNA methyltransferases, which are generally associated with gene suppression (Chen et al., 2021). The Notch pathway maintains essential NSCs and hippocampal neurogenesis, and its receptor promotes NSC proliferation (Gonçalves et al., 2016). Moreover, the Notch ligand Delta-like protein 3 (DLL3) regulates the expression of Notch1 and maintain NSC proliferation. A decrease in Tet1 expression induces hypermethylation of the Notch signalling gene, inhibits transcriptional activation, and blocks the proliferation of NSCs (Chen et al., 2021). However, it is unclear whether the regulation of DLL3 and Notch1 by Tet1 is related to depression.

In this study, we investigated the effect on hippocampal neurogenesis of Tet1 regulation of the methylation levels of DLL3 and Notch1 to verify whether this mechanism plays a role in depression. We verified our hypothesis by constructing a mouse model of chronic social defeat stress (CSDS)-induced depression and using the Cre system to overexpress Tet1 protein in the mouse hippocampus.