Article

Cranial Irradiation Alters the Behaviorally Induced Immediate-Early Gene Arc (Activity-Regulated Cytoskeleton-Associated Protein)

Brain and Spinal Injury Center, Department of Physical Therapy and Rehabilitation Sciences, University of California, San Francisco, San Francisco, California 94110, USA.
Cancer Research (Impact Factor: 9.33). 01/2009; 68(23):9763-70. DOI: 10.1158/0008-5472.CAN-08-1861
Source: PubMed

ABSTRACT

Therapeutic irradiation of the brain is commonly used to treat brain tumors but can induce cognitive impairments that can severely affect quality of life. The underlying mechanisms responsible for radiation-induced cognitive deficits are unknown but likely involve alterations in neuronal activity. To gain some mechanistic insight into how irradiation may affect hippocampal neurons known to be associated with cognitive function, we quantitatively assessed the molecular distribution of the behaviorally induced immediate-early gene Arc (activity-regulated cytoskeleton-associated protein) at the level of mRNA and the protein. Young adult C57BL/6J mice received whole-brain irradiation with 0 or 10 Gy, and 1 week or 2 months later, exploration of a novel environment was used to induce Arc expression. The fractions of neurons expressing Arc mRNA and Arc protein were detected using fluorescence in situ hybridization and immunocytochemistry, respectively. Our results showed that there was a significant reduction in the percentage of neurons expressing Arc protein 1 week after irradiation, whereas 2 months after irradiation, there was a reduction in the percentage of neurons expressing both Arc mRNA and Arc protein. Importantly, radiation-induced changes in Arc expression were not a result of neuronal cell loss. The changes observed at 2 months were associated with a significant increase in the number of activated microglia, supporting the idea that inflammation may contribute to neuronal dysfunction. These findings are the first to show that local brain irradiation initiates changes in hippocampal neurons that disrupt the activity patterns (Arc expression) associated with neuroplasticity and memory.

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Available from: John R Fike, Mar 21, 2014
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    • "Interestingly, in a previous study we showed that mice that received head-only 56 Fe (1 Gy) irradiation showed a lower fraction of neurons expressing activity-regulated cytoskeleton-associated protein (Arc) in the free blade of the dentate gyrus than sham-irradiated mice [34]. Together, these data suggest that neurons normally showing increased spine density following exploratory behavior and having this ability being affected by 56 Fe irradiation might be expressing the immediate early gene Arc that is enriched in neuronal dendrites [39] and affected by cranial irradiation [40]. The trend toward a behavioral testing × radiation interaction for apical dendrites in the CA3 region of the hippocampus is remarkable based on the retraction and simplification of apical dendrites in the CA3 region of the hippocampus following chronic restraint stress [41,42]. "
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    • "The underlying mechanisms responsible for radiationinduced cognitive impairment remain, however, elusive. The possible mechanism includes alterations in the neurogenic cell populations in GD (Rola et al. 2004; Winocur et al. 2006; Monje and Palmer 2003; Saxe et al. 2006), loss of mature neurons in GD (Raber et al. 2004; Fan et al. 2007), alterations in NMDA receptor subunits (Shi et al. 2006), genetic risk factors (Villasana et al. 2006) and lower expression of the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein) (Rosi et al. 2008). These cognitive dysfunctions often manifest as deficits in hippocampal-dependent learning and memory, including spatial information processing (Abayomi 1996; Crossen et al. 1994; Roman and Sperduto 1995; Surma-aho et al. 2001). "
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    • "Specifically, irradiation of the temporal lobe can profoundly affect the cellular structures mediating learning and memory [2]–[4]. Ionizing radiation has been consistently shown to affect multiple neuroinflammatory signaling cascades [5]–[7] ultimately causing disruptions in hippocampal function [3]–[5], [8], [9]. Importantly, broad-spectrum anti-inflammatory treatment has been shown to abrogate certain aspects of radiation-induced hippocampal functional deficits [4], [9]. "
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