Abstract
Cranial irradiation is the main therapeutic treatment for primary and metastatic malignancies in the brain. However, cranial radiation therapy produces long-term impairment in memory, information processing, and attention that contribute to a decline in quality of life. The hippocampal neural network is fundamental for proper storage and retrieval of episodic and spatial memories, suggesting that hippocampal signaling dysfunction could be responsible for the progressive memory deficits observed following irradiation. Previous rodent studies demonstrated that irradiation induces significant loss in dendritic spine number, alters spine morphology, and is associated with behavioral task deficits. Additionally, the literature suggests a common mechanism in which synaptic elimination via microglial-mediated phagocytosis is complement dependent and associated with cognitive impairment in aging as well as disease. We demonstrate sexual dimorphisms in irradiation-mediated alterations of microglia activation markers and dendritic spine density. Further, we find that the significant dendritic spine loss observed in male mice following irradiation is microglia complement receptor 3 (CR3)-dependent. By identifying sex-dependent cellular and molecular factors underlying irradiation-mediated spine loss, therapies can be developed to counteract irradiation-induced cognitive decline and improve patient quality of life.
Highlights
Cranial irradiation is the main therapeutic treatment for primary and metastatic malignancies in the brain
To investigate the possible link between microglia and synaptic complexity following cranial radiation, we focused on the hippocampus; a critical structure involved in learning and memory, and investigated irradiation-mediated effects on microglial activation and neuronal structure in male and female mice
We demonstrate in the hippocampal molecular layer 30 d post-irradiation that: i) there was little change in microglia morphology; ii) CD68 and CD11b immunoreactivity was up-regulated in male Thy1+ and complement receptor 3 (CR3)-KO mice; iii) there was a significant loss of spine density in male Thy1+ mice with enhanced vulnerability of immature spine populations; and iv) spine loss did not occur in CR3-KO male mice
Summary
Cranial irradiation is the main therapeutic treatment for primary and metastatic malignancies in the brain. The literature suggests a common mechanism in which synaptic elimination via microglialmediated phagocytosis is complement dependent and associated with cognitive impairment in aging as well as disease. The resident immune macrophages of the central nervous system (CNS), are intricately branched and respond rapidly to pathological changes in the brain parenchyma such as excitotoxicity, neurodegenerative insults, ischemia, and direct tissue damage[4,5] Their response consists of actively moving towards the damage site, engulfing debris, and eliminating cell components following death. Increased C1q and C3d deposits at synapses that localized within microglial processes were detected in post-mortem multiple sclerosis brain tissue[19] These results suggest a common mechanism whereby synaptic elimination via microglial-mediated phagocytosis is complement dependent and associated with cognitive impairment in aging and disease. Abnormalities in spine morphology have been described in several conditions associated with cognitive decline; including, Alzheimer’s disease, Huntington disease, autism, and aging[24]
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