Deficiency of the Microglial Receptor CX3CR1 Impairs Postnatal Functional Development of Thalamocortical Synapses in the Barrel Cortex

“…be that MGCs, once inside TCA clusters, could contribute to the selection of synapses with a mature signature of their glutamate receptors (Yashiro and Philpot, 2008) by pruning immature synapses through phagocytosis (Paolicelli et al., 2011) in a complement-dependent manner (Schafer et al., 2012).”

“In the diseased adult CNS, several signaling pathways control the recruitment of microglia at sites of compromised homeostasis (Hanisch and Kettenmann, 2007; Ransohoff and Perry, 2009).”

“In few experiments heterozygous CX3CR1 /eGFP mice of either sex were obtained by crossing CX3CR1 eGFP/eGFP (Jung et al., 2000) with wild-type C57BL/6J mice (Janvier).”

“In the diseased adult CNS, several signaling pathways control the recruitment of microglia at sites of compromised homeostasis (Hanisch and Kettenmann, 2007; Ransohoff and Perry, 2009).”

“This chemokine is expressed by neurons; its receptor CX3CR1 is only expressed by MGCs and controls their migration and functions (Harrison et al., 1998; Maciejewski-Lenoir et al., 1999; Cardona et al., 2006; Ruitenberg et al., 2008; Liang et al., 2009; Paolicelli et al., 2011).”

“…local role of fractalkine in which cellular elements localized within the barrel hollows, possibly thalamic fibers, overexpress the chemokine at P5–P7 and thus favor directed migration of microglia (Harrison et al., 1998; Maciejewski-Lenoir et al., 1999) toward maturating thalamocortical synapses.”

“In rodents, experimental evidence shows that MGCs contribute to developmentally regulated neuronal apoptosis but also to synapse pruning (Mallat et al., 2005; Pont-Lezica et al., 2011; Schlegelmilch et al., 2011; Tremblay et al., 2011).”

“Although macrophages are known to influence the development of peripheral organs, the idea that brain resident macrophages could play a role during CNS development is relatively new (Erblich et al., 2011; Pont-Lezica et al., 2011; Schlegelmilch et al., 2011).”

“Several studies on adult rodents have reported that CX3CL1/R1 signaling, probably by controlling the activation state of MGCs, has an impact on functional properties and plasticity of hippocampal glutamate synapses (Ragozzino et al., 2006; Maggi et al., 2011; Rogers et al., 2011).”

“In parallel, several functional parameters of thalamocortical synapses evolve between P4 and the end of the second postnatal week (López-Bendito and Molnár, 2003; Daw et al., 2007; Inan and Crair, 2007).”

“…local role of fractalkine in which cellular elements localized within the barrel hollows, possibly thalamic fibers, overexpress the chemokine at P5–P7 and thus favor directed migration of microglia (Harrison et al., 1998; Maciejewski-Lenoir et al., 1999) toward maturating thalamocortical synapses.”

“In humans, description of the spatiotemporal organization of microglia in the embryonic and fetal CNS suggests that these cells play active roles in developmental processes (Verney et al., 2010).”

“This chemokine is expressed by neurons; its receptor CX3CR1 is only expressed by MGCs and controls their migration and functions (Harrison et al., 1998; Maciejewski-Lenoir et al., 1999; Cardona et al., 2006; Ruitenberg et al., 2008; Liang et al., 2009; Paolicelli et al., 2011).”

“In tangential sections through layer 4 at P4 and P5, the first stages at which barrels can be identified (Rebsam et al., 2002), we observed that MGCs remained mostly outside clusters of TCAs (Fig.”

“In parallel, several functional parameters of thalamocortical synapses evolve between P4 and the end of the second postnatal week (López-Bendito and Molnár, 2003; Daw et al., 2007; Inan and Crair, 2007).”

“Several studies on adult rodents have reported that CX3CL1/R1 signaling, probably by controlling the activation state of MGCs, has an impact on functional properties and plasticity of hippocampal glutamate synapses (Ragozzino et al., 2006; Maggi et al., 2011; Rogers et al., 2011).”

“In these mice, however, this modification which results from a transient impairment of microglia-neuron interactions during embryonic life is observed at excitatory synapses of mature animals (Roumier et al., 2008).”

“In rodents, experimental evidence shows that MGCs contribute to developmentally regulated neuronal apoptosis but also to synapse pruning (Mallat et al., 2005; Pont-Lezica et al., 2011; Schlegelmilch et al., 2011; Tremblay et al., 2011).”

“Several studies on adult rodents have reported that CX3CL1/R1 signaling, probably by controlling the activation state of MGCs, has an impact on functional properties and plasticity of hippocampal glutamate synapses (Ragozzino et al., 2006; Maggi et al., 2011; Rogers et al., 2011).”

“In rodents, experimental evidence shows that MGCs contribute to developmentally regulated neuronal apoptosis but also to synapse pruning (Mallat et al., 2005; Pont-Lezica et al., 2011; Schlegelmilch et al., 2011; Tremblay et al., 2011).”

“Thalamocortical (TC) slices (400 m) from P5 to P33 mice were prepared as previously described (Laurent et al., 2002) in an ice-cold solution containing (in mM): 215 sucrose, 2.5 KCl, 1.25 NaH2PO4, 26 NaHCO3, 20 glucose, 5 pyruvate, 1 CaCl2 and 7 MgCl2, bubbled with carbogene, pH 7.4, 310 mOsm.”

“In rodents, experimental evidence shows that MGCs contribute to developmentally regulated neuronal apoptosis but also to synapse pruning (Mallat et al., 2005; Pont-Lezica et al., 2011; Schlegelmilch et al., 2011; Tremblay et al., 2011).”

“Alternatively, signaling molecules such as interleurkin-1 , tumor necrosis factor- or brain-derived neurotrophic factor, known to be released by microglia, can modulate the expression and the function of glutamate receptors (Beattie et al., 2002; Chao, 2003; Zhang et al., 2010; Zhong et al., 2010).”

“In parallel, several functional parameters of thalamocortical synapses evolve between P4 and the end of the second postnatal week (López-Bendito and Molnár, 2003; Daw et al., 2007; Inan and Crair, 2007).”

“It resembles that of microglia around glomeruli of the developing olfactory bulb (Fiske and Brunjes, 2000) and indicates that MGC colonization of layer 4 does not proceed randomly.”

“Finally, MGCs probably also influence other aspects of barrel maturation such as the rearrangement of dendrites of layer 4 cells and the removal of subplate cell neurites which occurs at the end of the first postnatal week (Hoerder-Suabedissen and Molnár, 2012).”

“This chemokine is expressed by neurons; its receptor CX3CR1 is only expressed by MGCs and controls their migration and functions (Harrison et al., 1998; Maciejewski-Lenoir et al., 1999; Cardona et al., 2006; Ruitenberg et al., 2008; Liang et al., 2009; Paolicelli et al., 2011).”

“Alternatively, signaling molecules such as interleurkin-1 , tumor necrosis factor- or brain-derived neurotrophic factor, known to be released by microglia, can modulate the expression and the function of glutamate receptors (Beattie et al., 2002; Chao, 2003; Zhang et al., 2010; Zhong et al., 2010).”

“CX3CR1-CX3CL1 interactions are also required for functional maturation of thalamocortical synapses (72).”

“Recent work has shown that mice lackingCX3CR1 have delayed invasion of the cortical barrel fields by microglia, and a transient delay in the normally observed AMPA receptor subunit switching in thalamocortical barrel cortex synapses (Hoshiko et al., 2012).”