Abnormal FKN-CX3CR1-NR signal triggers hippocampal synaptic dysfunction in rheumatoid arthritis-related depression

Rheumatoid arthritis-related depression (RAD) is a major depressive disorder with high morbidity and disability rate. Our previous studies have shown that FKN/CX3CR1 signal axis led to observable depressive-like behaviors in RAD rats. Emerging evidence indicates that abnormal activated NMDA receptors and failed resilience of hippocampal plasticity contribute to the onset of depression. However, the underlying neural mechanisms of RAD remain unclear. We hypothesized that RAD might be associated with the hippocampal synaptic dysfunction, triggered by FKN-CX3CR1-NR signal pathway. To test this hypothesis, here we employed RAD model in vivo and in vitro and found that RAD rats exhibited a FKN level elevation with obvious features of rheumatoid arthritis and depressive-like behaviors. In addition, RAD modeling markedly destroyed the brain microvascular and activated microglia, eventually leading to hippocampal synaptic dysfunction and monoamine neurotransmitter deficiency via abnormal CX3CR1-NR signal pathway. Further in vitro study also indicated that the simulated RAD conditions resulted in synaptic damage of hippocampal neuron with abnormal levels of FKN and monoamine neurotransmitter, and then the activated CX3CR1-NR signal pathway caused microglia activation followed by hippocampal neuron synaptic dysfunction. Interestingly, both CX3CR1 receptor agonist (fractalkine) and NR receptor agonist (NMDA) aggravated the hippocampal synaptic dysfunction and monoamine neurotransmitter deficiency in RAD rats and in simulated RAD conditions. In contrast, both CX3CR1 receptor blocker (AZD8797) and NR receptor blocker (MK-801) ameliorated the FKN-CX3CR1-NR signal-driven microglia activation, hippocampal synaptic dysfunction and depressive-like behaviors in RAD rats. Collectively, these findings unveiled that the microglia activation-driven hippocampal synaptic dysfunction, triggered by abnormal FKN-CX3CR1-NR signal pathway, is responsible for depressive-like behaviors in RAD rats. The current results provide promising molecular targets and strategy for the treatment of RAD.