Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress

Abstract Chronic stress is one of the most relevant triggering factors for major depression. Microglial cells are highly sensitive to stress and, more generally, to environmental challenges. However, the role of these brain immune cells in mediating the effects of stress is still unclear. Fractalkine signaling – which comprises the chemokine CX 3 CL1, mainly expressed by neurons, and its receptor CX 3 CR1, almost exclusively present on microglia in the healthy brain – has been reported to critically regulate microglial activity. Here, we investigated whether interfering with microglial function by deleting the Cx 3 cr1 gene affects the brain’s response to chronic stress. To this purpose, we housed Cx 3 cr1 knockout and wild-type adult mice in either control or stressful environments for 2 weeks, and investigated the consequences on microglial phenotype and interactions with synapses, synaptic transmission, behavioral response and corticosterone levels. Our results show that hampering neuron–microglia communication via the CX 3 CR1–CX 3 CL1 pathway prevents the effects of chronic unpredictable stress on microglial function, short- and long-term neuronal plasticity and depressive-like behavior. Overall, the present findings suggest that microglia-regulated mechanisms may underlie the differential susceptibility to stress and consequently the vulnerability to diseases triggered by the experience of stressful events, such as major depression.