Pharmacologic Manipulation of Complement Receptor 3 Prevents Dendritic Spine Loss and Cognitive Impairment After Acute Cranial Radiation

Purpose Cranial irradiation induces healthy tissue damage that can lead to neurocognitive complications, negatively impacting patient quality of life. One damage indicator associated with cognitive impairment is loss of neuronal spine density; we previously have demonstrated that irradiation-mediated spine loss is microglial complement receptor 3 (CR3) and sex-dependent. In this study, we hypothesized that these changes are associated with late-delayed cognitive deficits and amenable to pharmacologic intervention. Methods and Materials Our model of cranial irradiation (acute, 10 Gy gamma) used male and female CR3-wild-type and -deficient Thy-1 YFP mice on the C57BL/6 background. Thirty days post-irradiation, following behavioral testing, we quantified spine density and markers of microglial reactivity in the hippocampal dentate gyrus. In a separate experiment, male Thy-1 YFP C57BL/6 mice were treated with leukadherin-1 (LA1), a modulator of CR3 function. Results We found that male mice demonstrate irradiation-mediated spine loss and cognitive deficits whereas female and CR3 knockout mice do not. These changes were associated with greater reactivity of microglia in male mice. Moreover, pharmacological manipulation of CR3 with LA1 prevented spine loss and cognitive deficits in irradiated male mice. Conclusions This work improves our understanding of irradiation-mediated mechanisms and sexual dimorphic responses and may help identify novel therapeutics to reduce irradiation-induced cognitive decline and improve patient quality of life.