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

ABSTRACT

PURPOSE: Cranial irradiation induces healthy tissue damage that can lead to neurocognitive complications, negatively affecting patient quality of life. One damage indicator associated with cognitive impairment is loss of neuronal spine density. We previously demonstrated that irradiation-mediated spine loss is microglial complement receptor 3 (CR3) and sex dependent. 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 CR3-deficient Thy-1 YFP mice of C57BL/6 background. Forty-five days after irradiation and 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, a modulator of CR3 function. RESULTS: We found that male mice demonstrate irradiation-mediated spine loss and cognitive deficits but that female and CR3 knockout mice do not. These changes were associated with greater reactivity of microglia in male mice. Pharmacologic 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 sex dependent responses and may help identify novel therapeutics to reduce irradiation-induced cognitive decline and improve patient quality of life.