MeCP2 Modulates Depression-Like Behaviors Comorbid to Chronic Pain by Regulating Adult Hippocampal Neurogenesis

Although previous studies have revealed the association between chronic pain-induced depression and defective adult hippocampal neurogenesis (AHN), the underlying molecular mechanism remains elusive. This study aims to examine the association between AHN and depression-like behaviors, and to reveal the underlying mechanisms.

The chronic neuropathic pain model was established using mice with the spared nerve injury (SNI) surgery. The depression-like behaviors were evaluated by using the sucrose preference test (SPT), the tail suspension test (TST), the forced swimming test (FST), and the open field test (OFT). The expression of Methyl-CpG-binding protein 2 (MeCP2) was modulated by injecting the adeno-associated virus (AAV) with the DIO system into the ventral DG of the Nes-CreER^T2 mice. The miRNAs in hippocampal neural stem cells (NSCs) of mice with chronic pain were analyzed via miRNA sequencing.

We found that MeCP2, an epigenetic factor that plays a key role in the development of neurons, was significantly down-regulated in NSCs in the dentate gyrus (DG) of the hippocampus in adult mice with chronic pain and comorbid depression, suggesting a role of MeCP2 in the regulation of depression-like behavior induced by chronic neuropathic pain. MeCP2 expression levels in hippocampal NSCs were closely related to AHN and chronic pain comorbid depression, and miR-199b-3p specifically targeted and inhibited MeCP2 expression by directly interacting with its 3'-UTR sequence. Furthermore, we demonstrated that the increased level of miR-199b-3p in NSCs after the occurrence of chronic pain was responsible for AHN inhibition and comorbid depression.

Chronic neuropathic pain may result in an increased level of miR-199b-3p in hippocampal NSCs, which in turn targeted the Mecp2 gene and inhibited its transcription. Inhibited MeCP2 expression in NSCs contributes to AHN inhibition and depression-like behaviors.