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Whole brain irradiation in mice causes long-term impairment in astrocytic calcium signaling but preserves astrocyte-astrocyte coupling

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Abstract

Whole brain irradiation (WBI) therapy is an important treatment for brain metastases and potential microscopic malignancies. WBI promotes progressive cognitive dysfunction in over half of surviving patients, yet, the underlying mechanisms remain obscure. Astrocytes play critical roles in the regulation of neuronal activity, brain metabolism, and cerebral blood flow, and while neurons are considered radioresistant, astrocytes are sensitive to γ-irradiation. Hallmarks of astrocyte function are the ability to generate stimulus-induced intercellular Ca2+ signals and to move metabolic substrates through the connected astrocyte network. We tested the hypothesis that WBI-induced cognitive impairment associates with persistent impairment of astrocytic Ca2+ signaling and/or gap junctional coupling. Mice were subjected to a clinically relevant protocol of fractionated WBI, and 12 to 15 months after irradiation, we confirmed persistent cognitive impairment compared to controls. To test the integrity of astrocyte-to-astrocyte gap junctional coupling postWBI, astrocytes were loaded with Alexa-488-hydrazide by patch-based dye infusion, and the increase of fluorescence signal in neighboring astrocyte cell bodies was assessed with 2-photon microscopy in acute slices of the sensory-motor cortex. We found that WBI did not affect astrocyte-to-astrocyte gap junctional coupling. Astrocytic Ca2+ responses induced by bath administration of phenylephrine (detected with Rhod-2/AM) were also unaltered by WBI. However, an electrical stimulation protocol used in long-term potentiation (theta burst), revealed attenuated astrocyte Ca2+ responses in the astrocyte arbor and soma in WBI. Our data show that WBI causes a long-lasting decrement in synaptic-evoked astrocyte Ca2+ signals 12–15 months postirradiation, which may be an important contributor to cognitive decline seen after WBI.

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Funding

This work was supported by grants from the Oklahoma Center for the Advancement of Science and Technology, the National Institute on Aging (R01-AG047879; R01-AG055395), the National Institute of Neurological Disorders and Stroke (R01-NS056218, R01-NS100782), the Cellular and Molecular GeroScience CoBRE (P20GM125528) and the Canadian Institutes of Health Research, Foundation Grant (FDN-148471). G.R.G. was supported by Canada Research Chairs.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Cumming School of Medicine, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada

    Adam Institoris, Ciaran Murphy-Royal, Jordan N. Haidey & Grant R. Gordon

  2. Department of Biochemistry and Molecular Biology, Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Oklahoma Center for Geroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Stefano Tarantini, Andriy Yabluchanskiy, Anna Csiszar & Zoltan Ungvari

  3. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary

    Stefano Tarantini & Zoltan Ungvari

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  1. Adam Institoris
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Correspondence to Grant R. Gordon.

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Institoris, A., Murphy-Royal, C., Tarantini, S. et al. Whole brain irradiation in mice causes long-term impairment in astrocytic calcium signaling but preserves astrocyte-astrocyte coupling. GeroScience 43, 197–212 (2021). https://doi.org/10.1007/s11357-020-00289-8

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