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CCR2 Deficiency Prevents Neuronal Dysfunction and Cognitive Impairments Induced by Cranial Irradiation

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Published OnlineFirst December 13, 2012; DOI: 10.1158/0008-5472.CAN-12-2989 Cancer Therapeutics, Targets, and Chemical Biology Research CCR2 Deficiency Prevents Neuronal Dysfunction and Cognitive Impairments Induced by Cranial Irradiation Karim Belarbi1,2, Timothy Jopson1,2, Carla Arellano1,2, John R. Fike1,3, and Susanna Rosi1,2,3 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 (À/À) 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- À À 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. Cancer Res; 73(3); 1201–10. Ó2012 AACR. Introduction approaches or strategies to treat this serious complication Ionizing radiation is a first-line treatment of intracranial can be developed. malignancies. However, cranial irradiation can induce a pro- While high-radiation doses can lead to serious damage gressive and long-lasting decline in cognition that can severely involving tissue destruction (7), the mechanisms underlying impact the quality of life (1, 2). Such deficits can manifest in lower dose radiation-induced cognitive impairments are likely humans and experimental models as hippocampus-dependent to be subtle and multifactorial. Important possibilities include impairments that involve spatial information processing (3, 4). alterations in the neurogenic cell populations in the dentate It has been suggested that the severity of cognitive impairment gyrus (3, 8, 9) as well as changes in functional activation of in humans depends upon the dose of radiation delivered to the neuronal networks of the hippocampus (10). New neurons medial temporal lobes (1), where the hippocampus is located. (adult-born) are generated in the subgranular zone of the Given the growing population of long-term survivors of intra- dentate gyrus (11) and migrate into the granule cell layer, – cranial tumor, quality of life has become an increasing concern where they integrate into hippocampal networks (12 14) and (2). Currently, there are no successful treatments or prevention contribute to hippocampal function (15, 16). We and others strategies for radiation-induced cognitive impairments, and have shown that ionizing irradiation reduces the production of only a few possibilities have been suggested (5, 6). Therefore, adult-born neurons (3, 8, 12, 17), alters the distribution of there is a need to more fully understand the pathogenesis remaining adult-born neurons throughout the granule cell layer of cognitive dysfunctions after irradiation so that new (12), and disrupts the activity patterns associated with neuro- plasticity in hippocampal neurons (10). Importantly, several studies suggest that inflammatory factors may adversely affect adult neurogenesis (13, 18, 19), contribute to the disruption of Authors' Affiliations: 1Brain and Spinal Injury Center; Departments of neuronal function, and negatively impact accuracy of hippo- 2Physical Therapy Rehabilitation Science and 3Neurological Surgery, Uni- – versity of California, San Francisco, San Francisco, California campal network activity (20 22) and cognitive function (23). Taken together, data from a number of laboratories suggest Corresponding Author: Susanna Rosi, Brain and Spinal Injury Center, San fl Francisco General Hospital, University of California San Francisco, 1001 that in ammation may play a causal if not contributory role in Potrero Ave, Bld#1, Room#101, San Francisco, CA 94110. Phone: 415- the pathogenesis of radiation induced cognitive deficits. 206-3708, ext. 8747; Fax: 415-206-3948; E-mail: [email protected] Because of their ability to regulate immune cell activation doi: 10.1158/0008-5472.CAN-12-2989 (24), chemokine receptors and their ligands are considered Ó2012 American Association for Cancer Research. essential mediators of postinjury neuroinflammation. Cells of www.aacrjournals.org 1201 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst December 13, 2012; DOI: 10.1158/0008-5472.CAN-12-2989 Belarbi et al. the monocyte-macrophage lineage, including microglia, arena (60 cm  60 cm with 20 cm high walls) was placed in a express the chemokine (C–C motif) receptor (CCR) 2 (25– dimly lit behavioral testing room. Large visual cues were placed 27) and studies using CCR2 knockout mice have shown its on the walls of the testing room at various locations to provide crucial and nonredundant role in peripheral macrophage spatial points of reference. Mice were allowed to explore the infiltration at the sites of injury in the central nervous system open field arena for 1 5-minute period for 4 consecutive days (CNS; refs. 28–30). Moreover, CCR2 is also expressed by neural (habituation phase). On day 5, 3 identical objects were placed progenitors (31) and by mature granular and pyramidal neu- in the arena and mice were allowed to explore them for 4 10- rons of the hippocampus (32, 33) and could therefore modulate minute periods (familiarization phase). Mice were then placed both neurogenesis and neuronal function in the hippocampus. back in their cage for 4 minutes. One of the objects was then In addition, CCR2 has been shown to play a role in the replaced with a novel object and mice were reintroduced into pathogenic processes in several models of neurologic disorders the open arena to explore for 3 minutes. Trials were recorded (29, 34, 35). Given those data, it is conceivable that after brain using an overhead camera and live tracking of the animals was irradiation CCR2 signaling may have an important influence on achieved using an automated video tracking system (Ethovi- inflammation, neurogenesis, hippocampal neuronal activity, sion XT; Noldus Information Technology). Exploratory behav- and cognitive functions. To test this hypothesis, we used our ior was defined as the animal directing its nose toward an well-established mouse model of cranial irradiation object at a distance of less than 4 cm. Data were expressed as (3, 8, 10, 36) and measured cognitive functions, expression of the percentage time spent exploring the novel object relative to inflammatory cytokines and their receptors, macrophage/ the total time spent exploring all the objects. The objects were microglia activation, adult neurogenesis, and hippocampal secured to the floor using Velcro. The arena and objects were neuronal network activation in wild-type (WT) mice, and mice cleaned with 0.025% bleach between trials to minimize odor À À lacking CCR2 (CCR2 / ). cues. Materials and Methods Morris water maze Animal procedures Assessment of hippocampus-dependent cognitive perfor- This research was conducted in compliance with the United mance was conducted using the Morris water maze test (38). A States Department of Health and Human Services Guide for the plastic tank/pool (120-cm diameter) was placed in a dimly lit Care and Use of Laboratory Animals and with the University of behavioral testing room. Visual cues were placed around the California Institutional Animal Care and Use Committee. Two- room as spatial references. A transparent platform (10-cm À À month-old CCR2 / mice on a C57BL/6 background and wild- diameter) was placed in the tank and opaque water was added type C57BL/6 mice were purchased from The Jackson Labora- until the platform was submerged 1 cm below the surface. tory. All animals were anesthetized with an intraperitoneal (i.p.) Visible platform training took place on day 1, with a flag injection of a ketamine (100 mg/kg)/xylazine (10 mg/kg) mix- installed on the escape platform to allow the mouse to see ture, placed 16.3 cm from a cesium-137 source (J.L. Shepherd & the location of the platform. Each mouse conducted a total of 6 Associates). The body was shielded with a lead collimator visible platform trials, with the platform placed at different that limited the beam to a width of 1 cm. Irradiated animals locations in each trial. A mouse that failed to locate the À À (CCR2 / -IRR, n ¼ 10 and WT-IRR, n ¼ 10) were given a single platform within the allotted time was immediately guided to À À 10 Gy dose to the head only. Sham animals (CCR2 / -SH, n ¼ 10 the platform manually. Once the mouse reached the platform, and WT-SH, n ¼ 10) were treated identically without being it remained there for 20 seconds before removal from the water exposed to irradiation. Four weeks postirradiation, mice were maze. Hidden platform training took place on days 2 to 4. All injected with bromodeoxyuridine (BrdUrd; Sigma-Aldrich; 100 mice conducted 6 trials per day (18 trials total), and the tank mg/kg/d; i.p.; 7 days) to label cells synthesizing DNA. Mice were insertion point was changed randomly from trial to trial. The handled daily for 10 days before behavioral assessment.
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