MKP1 may be involved in the occurrence of depression by regulating hippocampal autophagy in rats.

BACKGROUND: Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP1) is upregulated in the hippocampus of patients with depression, while pharmacological inhibition of hippocampal MKP1 can mitigate depression-like behaviors in rodents. In addition, MAPK signaling regulates autophagy, and antidepressants were recently shown to target autophagic signaling pathways. We speculated that MKP1 contributes to depression by enhancing hippocampal autophagy through dephosphorylation of the MAPK isoform ERK1/2. METHODS: We established a rat depression model by exposure to chronic unpredictable mild stress (CUMS), and then examined depression-like behaviors in the sucrose preference test (SPT) and forced swimming test (FST) as well as expression changes in hippocampal MKP1, ERK1/2, phosphorylated ERK1/2, and autophagy-related proteins LC3II by Western blotting and immunostaining. These same measurements were repeated in rats exposed to CUMS following hippocampal infusion of a MKP1-targeted shRNA. Finally, the effects of MKP1 expression level on autophagy we examined in rat GMI-R1 microglia. RESULTS: CUMS-exposed rats demonstrated anhedonia in the SPT and helplessness in the FST, two core depression-like behaviors. Expression levels of MKP1 and LC3II were upregulated in the hippocampus of CUMS rats, suggesting enhanced autophagy, while pERK/ERK was downregulated. Knockdown of hippocampal MKP1 mitigated depression-like behaviors, downregulated hippocampal LC3II expression, and upregulated hippocampal pERK/ERK. Similarly, MKP1 knockdown in GMI-R1 cells upregulated pERK/ERK and reduced the number of LC3II autophagosomes, while MKP1 overexpression had the opposite effects. CONCLUSION: Enhanced hippocampal autophagy via MKP1-mediated ERK dephosphorylation may contribute to the development of depression.

Down-regulation of MKP-1 in hippocampus protects against stress-induced depression-like behaviors and neuroinflammation.

Chronic stress is the primary environmental risk factor for major depressive disorder (MDD), and there is compelling evidence that neuroinflammation is the major pathomechanism linking chronic stress to MDD. Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a negative regulator of MAPK signaling pathways involved in cellular stress responses, survival, and neuroinflammation. We examined the possible contributions of MKP-1 to stress-induced MDD by comparing depression-like behaviors (anhedonia, motor retardation, behavioral despair), neuroinflammatory marker expression, and MAPK signaling pathways among rats exposed to chronic unpredictable mild stress (CUMS), overexpressing MKP-1 in the hippocampus, and CUMS-exposed rats underexpressing MKP-1 in the hippocampus. Rats exposed to CUMS exhibited MKP-1 overexpression, greater numbers of activated microglia, and enhanced expressions of neuroinflammatory markers (interleukin [IL]-6, [IL]-1ß, tumor necrosis factor [TNF]-ɑ, and decreased phosphorylation levels of ERK and p38 in the hippocampus as well as anhedonia in the sucrose preference test, motor retardation in the open field, and greater immobility (despair) in the forced swimming tests. These signs of neuroinflammation and depression-like behaviors and phosphorylation levels of ERK and p38 were also observed in rats overexpressing MKP-1 without CUMS exposure, while CUMS-induced neuroinflammation, microglial activation, phosphorylation levels of ERK and p38, and depression-like behaviors were significantly reversed by MKP-1 knockdown. Moreover, MKP-1 knockdown promoted the activation of the MAPK isoform ERK, implying that the antidepressant-like effects of MKP-1 knockdown may be mediated by the ERK pathway disinhibition. These findings suggested that hippocampal MKP-1 is an essential regulator of stress-induced neuroinflammation and a promising target for antidepressant development.

Genome-wide meta-analysis, functional genomics and integrative analyses implicate new risk genes and therapeutic targets for anxiety disorders.

Anxiety disorders are the most prevalent mental disorders. However, the genetic etiology of anxiety disorders remains largely unknown. Here we conducted a genome-wide meta-analysis on anxiety disorders by including 74,973 (28,392 proxy) cases and 400,243 (146,771 proxy) controls. We identified 14 risk loci, including 10 new associations near CNTNAP5, MAP2, RAB9BP1, BTN1A1, PRR16, PCLO, PTPRD, FARP1, CDH2 and RAB27B. Functional genomics and fine-mapping pinpointed the potential causal variants, and expression quantitative trait loci analysis revealed the potential target genes regulated by the risk variants. Integrative analyses, including transcriptome-wide association study, proteome-wide association study and colocalization analyses, prioritized potential causal genes (including CTNND1 and RAB27B). Evidence from multiple analyses revealed possibly causal genes, including RAB27B, BTN3A2, PCLO and CTNND1. Finally, we showed that Ctnnd1 knockdown affected dendritic spine density and resulted in anxiety-like behaviours in mice, revealing the potential role of CTNND1 in anxiety disorders. Our study identified new risk loci, potential causal variants and genes for anxiety disorders, providing insights into the genetic architecture of anxiety disorders and potential therapeutic targets.

Enriched environment mitigates depressive behavior by changing the inflammatory activation phenotype of microglia in the hippocampus of depression model rats.

BACKGROUND: Inflammation mediated by microglia has been shown to be involved in the pathogenesis of depression. The enriched environment (EE) can improve depression-like behaviors and reduce inflammatory reactions, but it is unclear whether this is by changing the inflammatory activation phenotype of microglia. METHOD: A depression rat model was established using chronic unpredictable stress (CUS) for four weeks. The rats were then treated with EE or fluoxetine administration during the following three weeks. Behavior tests including sucrose preference, forced swimming and open field were applied to evaluate the depression-like behaviors of rats at the baseline period prior to CUS, the end of fourth week and at the end of the seventh week. Microglial activation and hippocampal neuro-inflammation were detected on postmortem using immunofluorescence, western blotting, and real-time polymerase reaction (PCR). RESULT: The results showed that severe depressive-like behavior was induced by four weeks of CUS. Changes in peripheral blood inflammatory cytokines were detected by ELISA. Immunofluorescent staining showed the IBA-1 of microglia activation marker level significantly increased in affected rats. The hippocampal microglial activation state was determined by measuring the increased levels of iNOS an M1 marker and the decreased levels of CD206, an M2 marker. The activation of NF-κB upregulation of inflammatory cytokines in the hippocampus and factors such as IL-10 were decreased. This study showed that EE and chronic fluoxetine treatment alleviated the depressive-like behavior induced by chronic stress and significantly inhibited microglial activation, activated NF-κB inflammasome and increased pro-inflammatory cytokines. CONCLUSION: EE can alleviate depression-like behavior by modulating the phenotype of microglia, inhibiting pro-inflammatory genes, and promoting anti-inflammatory genes. Furthermore, EE can effectively reduce the phosphorylation and expression levels of NF-κB.