title: CCR2 deficiency prevents neuronal dysfunction and cognitive impairments induced by cranial irradiation.
abstract: Cranial irradiation can lead to long-lasting cognitive impairments in patients receiving radiotherapy for the treatment of malignant brain tumors. Recent studies have suggested inflammation as a major contributor to these deficits; we determined if the chemokine (C-C motif) receptor 2 (CCR2) was a mediator of cognitive impairments induced by irradiation. Two-month-old male Ccr2 knockout (-/-) and wild-type mice received 10 Gy cranial irradiation or sham-treatment. One month after irradiation, bromodeoxyuridine was injected intraperitoneally for seven consecutive days to label newly generated cells. At two months postirradiation, cognitive function was assessed by novel object recognition and Morris water maze. Our results show that CCR2 deficiency prevented hippocampus-dependent spatial learning and memory impairments induced by cranial irradiation. Hippocampal gene expression analysis showed that irradiation induced CCR2 ligands such as CCL8 and CCR2 deficiency reduced this induction. Irradiation reduced the number of adult-born neurons in both wild-type and Ccr2(-/-) mice, but the distribution pattern of the adult-born neurons through the granule cell layer was only altered in wild-type mice. Importantly, CCR2 deficiency normalized the fraction of pyramidal neurons expressing the plasticity-related immediate early gene Arc. These data offer new insight into the mechanism(s) of radiation-injury and suggest that CCR2 is a critical mediator of hippocampal neuronal dysfunction and hippocampal cognitive impairments after irradiation. Targeting CCR2 signaling could conceivably provide an effective approach to reduce or prevent the incidence and severity of this serious side effect of ionizing irradiation.
authors.affiliation: Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Karim
authors.initials: K
authors.lastname: Belarbi
authors.forename: Timothy
authors.initials: T
authors.lastname: Jopson
authors.forename: Carla
authors.initials: C
authors.lastname: Arellano
authors.forename: John R
authors.initials: JR
authors.lastname: Fike
authors.forename: Susanna
authors.initials: S
authors.lastname: Rosi
mesh_terms: D000818:Animals; D054412:Chemokine CCL8 / Q000502:physiology; D003072:Cognition Disorders / Q000209:etiology* / Q000517:prevention & control; D016371:Cranial Irradiation / Q000009:adverse effects*; D003598:Cytoskeletal Proteins / Q000032:analysis; D006624:Hippocampus / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000032:analysis; D009474:Neurons / Q000502:physiology*; D054389:Receptors, CCR1 / Q000502:physiology; D054390:Receptors, CCR2 / Q000172:deficiency / Q000502:physiology*
chemical_list: C515454:Ccl8 protein, mouse; C515301:Ccr1 protein, mouse; C515335:Ccr2 protein, mouse; D054412:Chemokine CCL8; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D054389:Receptors, CCR1; D054390:Receptors, CCR2; C092069:activity regulated cytoskeletal-associated protein