Microglia and Their CX3CR1 Signaling Are Involved in Hippocampal- but Not Olfactory Bulb-related Memory and Neurogenesis

Recent studies demonstrate that microglia play an important role in cognitive and neuroplasticity processes, at least partly via microglial CX3C receptor 1 (CX3CR1) signaling. Furthermore, microglia are responsive to environmental enrichment (EE), which modulates learning, memory and neurogenesis. In the present study we examined the role of microglial CX3CR1 signaling in hippocampal- and olfactory-bulb (OB)-related memory and neurogenesis in homozygous mice with microglia-specific transgenic expression of GFP under the CX3CR1 promoter (CX3CR1(-/-) mice), in which the CX3CR1 gene is functionally deleted, as well as heterozygous CX3CR1(+/-) and WT controls. We report that the CX3CR1-deficient mice displayed better hippocampal-dependent memory functioning and olfactory recognition, along with increased number and soma size of hippocampal microglia, suggestive of mild activation status, but no changes in OB microglia. A similar increase in hippocampal-dependent memory functioning and microglia number was also induced by pharmacological inhibition of CX3CR1 signaling, using chronic (2weeks) i.c.v. administration of CX3CR1 blocking antibody. In control mice, EE improved hippocampal-dependent memory and neurogenesis, and increased hippocampal microglia number and soma size, whereas odor enrichment (OE) improved olfactory recognition and OB neurogenesis without changing OB microglia status. In CX3CR1-deficient mice, EE and OE did not produce any further improvement in memory functioning or neurogenesis and had no effect on microglial status. These results support the notion that in the hippocampus microglia and their interactions with neurons via the CX3CR1 play an important role in memory functioning and neurogenesis, whereas in the OB microglia do not seem to be involved in these processes.