Abstract
Microglia play important roles in perinatal neuro- and synapto-genesis. To test the role of microglia in these processes during adulthood, we examined the effects of microglia depletion, via treatment of mice with the CSF-1 receptor antagonist PLX5622, and abrogated neuronal-microglial communication in CX3C receptor-1 deficient (Cx3cr1-/-) mice. Microglia depletion significantly lowered spine density in young (developing) but not mature adult-born-granule-cells (abGCs) in the olfactory bulb. Two-photon time-lapse imaging indicated that microglia depletion reduced spine formation and elimination. Functionally, odor-evoked responses of mitral cells, which are normally inhibited by abGCs, were increased in microglia-depleted mice. In Cx3cr1-/- mice, abGCs exhibited reduced spine density, dynamics and size, concomitantly with reduced contacts between Cx3cr1-deficient microglia and abGCs' dendritic shafts, along with increased proportion of microglia-contacted spines. Thus, during adult neurogenesis, microglia regulate the elimination (pruning), formation, and maintenance of synapses on newborn neurons, contributing to the functional integrity of the olfactory bulb circuitry.
Highlights
Over the past decade it became evident that microglia play crucial roles in the regulation of synaptic processes (Tremblay et al, 2011; Wake et al, 2013), with important implications to normal behavior and to neuro- and psycho-pathology (Yirmiya and Goshen, 2011; Prinz and Priller, 2014; Chung et al, 2015; Yirmiya et al, 2015)
In the adult neurogenesis process, new neurons are constantly generated in the subventricular zone, migrate into the olfactory bulb (OB) via the rostral migratory stream (RMS), and upon their arrival begin to integrate into the existing neural circuits
The microglial depletion was evident in the transcriptional level, as revealed by a whole transcriptome RNA-seq analysis of OBs isolated from PLX5622-treated and their respective control mice
Summary
Over the past decade it became evident that microglia play crucial roles in the regulation of synaptic processes (Tremblay et al, 2011; Wake et al, 2013), with important implications to normal behavior and to neuro- and psycho-pathology (Yirmiya and Goshen, 2011; Prinz and Priller, 2014; Chung et al, 2015; Yirmiya et al, 2015). During the early postnatal brain development period, microglia were found to be important for synapse development. In the developing retino-geniculate system, microglia in the dorsal Lateral Geniculate Nucleus (dLGN) prune pre-synaptic terminals of the incoming retinal ganglion cells axons, contributing to the segregation of inputs into eye-specific territories (Schafer et al, 2012). One molecular system underlying neuronal-microglial interactions involves the microglial CX3C receptor-1 (CX3CR1) and its neuronallyderived CX3C Ligand-1 (CX3CL1) (Jung et al, 2000; Paolicelli et al, 2014; Pagani et al, 2015) During early postnatal development, CX3CR1 signaling plays a critical role in synaptic pruning. Microglia are involved in pruning of synapses on mature neurons.
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