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

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, radiationinduced 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.

Cranial irradiation compromises neuronal architecture in the hippocampus

“…Although their morphology varies widely, likely reflecting functional diversity, changes in spine density positively correlate with cognitive performance (31). The capability of dendritic spines to rapidly respond to transmembrane signals, including those associated with behavior, hormonal status, and synaptic activity and various forms of stress, indicate their critical role in learning and memory (32,33). The fact that radiation exposure leads to reduced spine density and, in particular, inhibits the formation of immature filopodia, is consistent with the adverse neurocognitive sequlae documented in brain cancer survivors subjected to cranial radiotherapy (1,34).…”

Dose- and ApoE Isoform-Dependent Cognitive Injury after Cranial56Fe Irradiation in Female Mice

“…Sweet et al (2014) found persistent (1 -12 months) decreases in ICAM-1 after ≥ 10 cGy whole-body irradiation of mice with 1 GeV/n protons with a pronounced sex difference; specifically, females were sensitive while males were not. Rosi et al (2008) and York et al (2012) found significant increases in activated microglia numbers (x-rays and protons) that were correlated with reductions in behaviorally-induced gene expression. Poulose et al (2011) observed astrocyte activation (rat hippocampus) after 16 O exposure accompanied by altered neurotrophic factor signaling, and Sanchez et al (2010) reported reductions in cultured human astrocyte glutamate transport following 1 H, 12 C, and 56 Fe irradiation.…”

“…The behaviorally-induced immediate early gene Arc was investigated by Rosi et al (2008Rosi et al ( , 2010 and Raber et al (2013) for its expression in the dentate gyrus of mice. Both messenger RNA and protein levels in neurons showed behaviorally-induced upregulation which was inhibited by exposure to X-rays and low doses of 56 Fe ions.…”

Radiation-induced brain injury: low-hanging fruit for neuroregeneration

“…34,46,73,89 Of particular therapeutic relevance are the effects of radiation on the oligodendrocytic lineage.…”