Microglial CX3CR1 promotes adult neurogenesis by inhibiting Sirt 1/p65 signaling independent of CX3CL1.
Sabine SellnerRicardo Paricio-MontesinosAlena SpießAnnette MasuchDaniel ErnyLaura A HarsanDominik V ElverfeldtMarius SchwabenlandKnut BiberOri StaszewskiSergio LiraSteffen JungMarco PrinzThomas BlankPublished in: Acta neuropathologica communications (2016)
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 hippocampus-dependent 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.
Keyphrases
- nuclear factor
- inflammatory response
- oxidative stress
- cerebral ischemia
- high fat diet induced
- toll like receptor
- neuropathic pain
- poor prognosis
- machine learning
- gene expression
- blood pressure
- insulin resistance
- acute myeloid leukemia
- spinal cord
- body composition
- dendritic cells
- small molecule
- young adults
- quantum dots
- cell death
- long non coding rna
- bone mineral density
- electronic health record
- functional connectivity