CTRP3 acts as a novel regulator in depressive-like behavior associated inflammation and apoptosis by meditating p38 and JNK MAPK signaling

Depression is a complicated etiological pattern, and its pathology and effective treatments are highly limited.C1q-tumor necrosis factor-related protein-3 (CTRP3) is an adipokine, playing crucial roles in metabolic regulatory properties. However, the effects of CTRP3 on depression are largely unknown. In the present study, we found that CTRP3 expression levels were markedly reduced in hippocampus of mice with depression induced by chronic unpredictable mild stress (CUMS). In mouse model with depression, CTRP3-deficient mice aggravated depression-associated behaviors, as evidenced by the reduced locomotor activity and sucrose consumption, while the elevated immobility time in the tail suspension test (TST) and forced swimming test (FST). Moreover, CUMS-induced neuron death and increased expression of cleaved Caspase-3 were significantly accelerated by CTRP3 knockout. Furthermore, CTRP3 deletion intensified pro-inflammatory response in CUMS-exposed mice, which was associated with the activation of nuclear factor-kappa B(NF-kappa B) signaling. The activity of mitogen-activated protein kinases (MAPKs), including p38 and JNK, was further promoted in hippocampus of CTRP3-knockout mice with CUMS exposure. In contrast,CTRP3 over-expression showed anti-apoptotic and anti-inflammatory effects in lipopolysaccharide (LPS)-treated microglial cells. Importantly, the in vitro experiments demonstrated that CTRP3 knockdown-exacerbated apoptosis and inflammatory response were remarkably abrogated by the blockage of p38 and JNK signaling pathways in microglia stimulated by LPS. Next, in CUMS exposed mice with CTRP3 deficiency, suppressing p38 and JNK markedly alleviated depressive-like behavior, hippocampal neuron death, apoptosis and inflammation. Therefore, CTRP3 may be an innovative therapeutic target for treating patients with depression through regulating p38 and JNK signaling.