Absence of microglial CX3CR1 impairs the synaptic integration of adult-born hippocampal granule neurons

Abstract

Microglia are immune cells that play a crucial role in maintaining brain homeostasis. Among the mechanisms of communication between microglia and neurons, the CX3CL1/CX3CR1 axis exerts a central modulatory role. Animals lacking CX3CR1 microglial receptor (CX3CR1-/- mice) exhibit marked alterations not only in microglia but also in neurons located in various regions of the brain. Here we show that microglial depletion of CX3CR1 leads to the deficient synaptic integration of adult-born granule neurons in the dentate gyrus (DG), both at the afferent and efferent level. Regarding the alterations in the former level, these cells show a reduced number of dendritic spines, which also exhibit morphological changes, namely enlargement and shortening. With respect to changes at the efferent level, these cells show a reduced area of axonal terminals. Both at the afferent and efferent level, synapses show ultrastructural enlargement, but they are depleted of synaptic vesicles, which suggests impaired functionality. We also show that selective increased microglial activation and extracellular matrix deposition in the zones in which the afferent synaptic contacts of these cells occur, namely in the molecular and the granule layer of the DG. In order to evaluate the impact of these structural alterations from a functional point of view, we performed a battery of behavioral tests related to hippocampal-dependent emotional behavior. We observed that female CX3CR1-/- mice exhibit a hyperactive, anxiolytic-like and depressive-like phenotype. These data shed light on novel aspects of the regulation of adult hippocampal neurogenesis by microglia that could be highly relevant for research into mood disorders.

Keywords: Adult hippocampal neurogenesis; CX3CR1; Connectivity; Extracellular matrix; Microglia; Retrovirus.