Microglial CX₃CR1 promotes adult neurogenesis by inhibiting Sirt 1/p65 signaling independent of CX₃CL1

Homo and heterozygote cx₃cr1 mutant mice, which harbor a green fluorescent protein (EGFP) in their cx₃cr1 loci, represent a widely used animal model to study microglia and peripheral myeloid cells. Here we report that microglia in the dentate gyrus (DG) of cx₃cr1^-/- mice displayed elevated microglial sirtuin 1 (SIRT1) expression levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) p65 activation, despite unaltered morphology when compared to cx₃cr1+/- or cx₃cr1+/+ controls. This phenotype was restricted to the DG and accompanied by reduced adult neurogenesis in cx₃cr1^-/- mice. Remarkably, adult neurogenesis was not affected by the lack of the CX3CR1-ligand, fractalkine (CX₃CL1). Mechanistically, pharmacological activation of SIRT1 improved adult neurogenesis in the DG together with an enhanced performance of cx₃cr1^-/- mice in a hippocampusdependent learning and memory task. The reverse condition was induced when SIRT1 was inhibited in cx₃cr1^-/- mice, causing reduced adult neurogenesis and lowered hippocampal cognitive abilities. In conclusion, our data indicate that deletion of CX3CR1 from microglia under resting conditions modifies brain areas with elevated cellular turnover independent of CX₃CL1.