Effects of 56Fe radiation on hippocampal function in mice deficient in chemokine receptor 2 (CCR2)
Departments of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR 97239, USA Behavioural brain research
(Impact Factor: 3.03).
03/2013; 246. DOI: 10.1016/j.bbr.2013.03.003
(56)Fe irradiation affects hippocampus-dependent cognition. The underlying mechanisms may involve alterations in neurogenesis, expression of the plasticity-related immediate early gene Arc, and inflammation. Chemokine receptor-2 (CCR2), which mediates the recruitment of infiltrating and resident microglia to sites of CNS inflammation, is upregulated by (56)Fe irradiation. CCR2 KO and wild-type mice were used to compare effects of (56)Fe radiation (600 MeV, 0.25Gy) on hippocampal function using contextual fear conditioning involving tone shock pairing during training (+/+) and exposure to the same environment without tone shock pairings (-/-). In the -/- condition, irradiation enhanced habituation in WT mice, but not CCR2 KO mice, suggesting that a lack of CCR2 was associated with reduced cognitive performance. In the++ condition, irradiation reduced freezing but there was no genotype differences. There were no significant correlations between the number of Arc-positive cells in the dentate gyrus and freezing in either genotype. While measures of neurogenesis and gliogenesis appeared to be modulated by CCR2, there were no effects of genotype on the total numbers of newly born activated microglia before or after irradiation, indicating that other mechanisms are involved in the genotype-dependent radiation response.
Available from: Knut Biber
- "There are thus various reports in which CCR2 expressing cells are suggested to be microglia (Abbadie et al., 2003; Zhang et al., 2007; Fernández-López et al., 2012) or described as microglia/macrophages (Yao and Tsirka, 2012) or referred to as amoeboid microglia cells (Deng et al., 2009). Often CCR2 is discussed to be an important receptor for the recruitment of microglia to injured brain areas (El Khoury et al., 2007; Zhang et al., 2007; Deng et al., 2009; Raber et al., 2013) and in this respect CCR2 has been described as receptor in spinal cord microglia that enables these cells to respond to peripheral nerve injury (Abbadie et al., 2003; Zhang et al., 2007). "
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ABSTRACT: The development of neuropathic pain in response to peripheral nerve lesion for a large part depends on microglia located at the dorsal horn of the spinal cord. Thus the injured nerve initiates a response of microglia, which represents the start of a cascade of events that leads to neuropathic pain development. For long it remained obscure how a nerve injury in the periphery would initiate a microglia response in the dorsal horn of the spinal cord. Recently, two chemokines have been suggested as potential factors that mediate the communication between injured neurons and microglia namely CCL2 and CCL21. This assumption is based on the following findings. Both chemokines are not found in healthy neurons, but are expressed in response to neuronal injury. In injured dorsal root ganglion cells CCL2 and CCL21 are expressed in vesicles in the soma and transported through the axons of the dorsal root into the dorsal horn of the spinal cord. Finally, microglia in vitro are known to respond to CCL2 and CCL21. Whereas the microglial chemokine receptor involved in CCL21-induced neuropathic pain is not yet defined the situation concerning the receptors for CCL2 in microglia in vivo is even less clear. Recent results obtained in transgenic animals clearly show that microglia in vivo do not express CCR2 but that peripheral myeloid cells and neurons do. This suggests that CCL2 expressed by injured dorsal root neurons does not act as neuron-microglia signal in contrast to CCL21. Instead, CCL2 in the injured dorsal root ganglia (DRG) may act as autocrine or paracrine signal and may stimulate first or second order neurons in the pain cascade and/or attract CCR2-expressing peripheral monocytes/macrophages to the spinal cord.
Frontiers in Cellular Neuroscience 08/2014; 8:210. DOI:10.3389/fncel.2014.00210 · 4.29 Impact Factor
Available from: Diego Gomez-Nicola
- " protect against loss of dopaminer - gic neurons in the striatum ( Kalkonde et al . , 2007 ) . More recently , CCR2 deficiency was shown to prevent hippocampus - dependent spatial learning and memory impair - ments induced by cranial irradiation , highlighting the poten - tial neuron - specific functions of this receptor ( Belarbi et al . , 2013 ; Raber et al . , 2013 ) . These contrasting views might be explained by alternative ligands , besides CCL2 : binding and signaling through CCR2 can be achieved by CCL2 , CCL7 , CCL8 , CCL12 , and CCL13 ( Bose and Cho , 2013 ) . For example , CCL8 was reported to elicit the CCR2 - mediated neuroprotective effects after irradiation ( Belarbi et al . , 2013 ) ."
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ABSTRACT: The expansion of the microglial population is one of the hallmarks of numerous brain disorders. The addition of circulating progenitors to the pool of brain macrophages can contribute to the progression of brain disease and needs to be precisely defined to better understand the evolution of the glial and inflammatory reactions in the brain. We have analyzed the degree of infiltration/recruitment of circulating monocytes to the microglial pool, in a prion disease model of chronic neurodegeneration. Our results indicate a minimal/absent level of CCR2-dependent recruitment of circulating monocytes, local proliferation of microglia is the main driving force maintaining the amplification of the population. A deficiency in CCR2, and thus the absence of recruitment of circulating monocytes, does not impact microglial dynamics, the inflammatory profile or the temporal behavioral course of prion disease. However, the lack of CCR2 has unexpected effects including the failure to recruit perivascular macrophages in diseased but not healthy CNS and a small reduction in microglia proliferation. These data define the composition of the CNS-resident macrophage populations in prion disease and will help to understand the dynamics of the CNS innate immune response during chronic neurodegeneration. GLIA 2014
Glia 07/2014; 62(7). DOI:10.1002/glia.22660 · 6.03 Impact Factor
Available from: Annette Masuch
- "On one hand there are various reports in which CCR2 expressing cells are suggested to be microglia (Abbadie et al., 2003; Zhang et al., 2007; Fernández-López et al., 2012) or described as microglia/macrophages (Yao and Tsirka, 2012) or referred to as amoeboid microglia cells (Deng et al., 2009). Often CCR2 is discussed to be an important receptor for the recruitment of microglia to injured brain areas (El Khoury et al., 2007; Zhang et al., 2007; Deng et al., 2009; Raber et al., 2013) and the inhibition or lack of CCR2 signaling is related to improved disease outcome (Abbadie et al., 2003; Dimitrijevic et al., 2007; Zhang et al., 2007; Fernández-López et al., 2012; Yao and Tsirka, 2012) implicating that CCR2-expressing microglia at least contribute to disease progression. "
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ABSTRACT: One long standing aspect of microglia biology was never questioned; their involvement in brain disease. Based on morphological changes (retracted processes and amoeboid shape) that inevitably occur in these cells in case of damage in the central nervous system, microglia in the diseased brain were called "activated." Because "activated" microglia were always found in direct neighborhood to dead or dying neuron, and since it is known now for more than 20 years that cultured microglia release numerous factors that are able to kill neurons, microglia "activation" was often seen as a neurotoxic process. From an evolutionary point of view, however, it is difficult to understand why an important, mostly post-mitotic and highly vulnerable organ like the brain would host numerous potential killers. This review is aimed to critically reconsider the term microglia neurotoxicity and to discuss experimental problems around microglia biology, that often have led to the conclusion that microglia are neurotoxic cells.
Frontiers in Cellular Neuroscience 05/2013; 7:71. DOI:10.3389/fncel.2013.00071 · 4.29 Impact Factor
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