Prevention of an increase in cortical ligand binding to AMPA receptors may represent a novel mechanism of endogenous brain protection by G-CSF after ischemic stroke

Article type: Research Article

Authors: Mammele, Stefan^{a; 1} | Frauenknecht, Katrin^{a; 1} | Sevimli, Sevgi^b | Diederich, Kai^b | Bauer, Henrike^a | Grimm, Christina^a | Minnerup, Jens^b | Schäbitz, Wolf-Rüdiger^{b; c} | Sommer, Clemens J.^{a; *}

Affiliations: [a] Institute of Neuropathology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany | [b] Department of Neurology, University of Münster, Germany | [c] Neurology, Bethel, EVKB, Bielefeld, Germany

Correspondence: [*] Corresponding author: Clemens J. Sommer, Institute of Neuropathology, Langenbeckstr. 1, 55131 Mainz, Germany. Tel.: +49 6131 17 7308; Fax: +49 6131 17 6606; E-mail: [email protected].

Note: [1] These authors contributed equally.

Abstract: Purpose: Using G-CSF deficient mice we recently demonstrated neuroprotective properties of endogenous G-CSF after ischemic stroke. The present follow-up study was designed to check, whether specific alterations in ligand binding densities of excitatory glutamate or inhibitory GABAA receptors may participate in this effect. Methods: Three groups of female mice were subjected to 45 minutes of MCAO: wildtype, G-CSF deficient and G-CSF deficient mice substituted with G-CSF. Infarct volumes were determined after 24 hours and quantitative in vitro receptor autoradiography was performed using [3H]MK-801, [3H]AMPA and [3H]muscimol for labeling of NMDA, AMPA and GABAA receptors, respectively. Ligand binding densities were analyzed in regions in the ischemic core, peri-infarct areas and corresponding contralateral regions. Results: Infarct volumes did not significantly differ between the experimental groups. Ligand binding densities of NMDA and GABAA receptors were widely in the same range. However, AMPA receptor binding densities in G-CSF deficient mice were substantially enhanced compared to wildtype mice. G-CSF substitution in mice lacking G-CSF largely reversed this effect. Conclusions: Although infarct volumes did not differ 24 hours after ischemia the increase of AMPA receptor binding densities in G-CSF deficient mice may explain the bigger infarcts previously observed at later time-points with the same stroke model.

Keywords: G-CSF, focal ischemia, MCAO, autoradiography, infarct volume, excitotoxicity, AMPA, mouse

DOI: 10.3233/RNN-150543

Journal: Restorative Neurology and Neuroscience, vol. 34, no. 4, pp. 665-675, 2016