CXCL10/CXCR3 signaling in glia cells differentially affects NMDA-induced cell death in CA and DG neurons of the mouse hippocampus.
The chemokine CXCL10 and its receptor CXCR3 are implicated in various CNS pathologies since interference with CXCL10/CXCR3 signaling alters the onset and progression in various CNS disease models. However, the mechanism and cell-types involved in CXCL10/CXCR3 signaling under pathological conditions are far from understood. Here, we investigated the potential role for CXCL10/CXCR3 signaling in neuronal cell death and glia activation in response to N-methyl-D-aspartic acid (NMDA)-induced excitotoxicity in mouse organotypic hippocampal slice cultures (OHSCs). Our findings demonstrate that astrocytes express CXCL10 in response to excitotoxicity. Experiments in OHSCs derived from CXCL10-deficient (CXCL10(-/-) ) and CXCR3-deficient (CXCR3(-/-) ) revealed that in the absence of CXCL10 or CXCR3, neuronal cell death in the CA1 and CA3 regions was diminished after NMDA-treatment when compared to wild type OHSCs. In contrast, neuronal cell death in the DG region was enhanced in both CXCL10(-/-) and CXCR3(-/-) OHSCs in response to a high (50 μM) NMDA-concentration. Moreover, we show that in the absence of microglia the differential changes in neuronal vulnerability between CXCR3(-/-) and wild type OHSCs are fully abrogated and therefore a prominent role for microglia in this process is suggested. Taken together, our results identify a region-specific role for CXCL10/CXCR3 signaling in neuron-glia and glia-glia interactions under pathological conditions.
van Weering
Hilmar R J
HR
Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen (UMCG), Rijksuniversiteit Groningen (RUG), Groningen, The Netherlands.
Boddeke
Hendrikus W G M
HW
Vinet
Jonathan
J
Brouwer
Nieske
N
de Haas
Alexander H
AH
van Rooijen
Nico
N
Thomsen
Allan R
AR
Biber
Knut P H
KP
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D054357:Chemokine CXCL10 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018891:Dentate Gyrus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000633:toxicity; D009457:Neuroglia / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D054367:Receptors, CXCR3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D016202:N-Methylaspartate