Astrocytic calcium release mediates peri-infarct depolarizations in a rodent stroke model
Cordula Rakers, Gabor C. Petzold
Cordula Rakers, Gabor C. Petzold
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Brief Report Neuroscience

Astrocytic calcium release mediates peri-infarct depolarizations in a rodent stroke model

Abstract

Stroke is one of the most common diseases and a leading cause of death and disability. Cessation of cerebral blood flow (CBF) leads to cell death in the infarct core, but tissue surrounding the core has the potential to recover if local reductions in CBF are restored. In these areas, detrimental peri-infarct depolarizations (PIDs) contribute to secondary infarct growth and negatively affect stroke outcome. However, the cellular pathways underlying PIDs have remained unclear. Here, we have used in vivo multiphoton microscopy, laser speckle imaging of CBF, and electrophysiological recordings in a mouse model of focal ischemia to demonstrate that PIDs are associated with a strong increase of intracellular calcium in astrocytes and neurons. We found that astroglial calcium elevations during PIDs are mediated by inositol triphosphate receptor type 2–dependent (IP3R2-dependent) release from internal stores. Importantly, Ip3r2-deficient mice displayed a reduction of PID frequency and overall PID burden and showed increased neuronal survival after stroke. These effects were not related to local CBF changes in response to PIDs. However, we showed that the release and extracellular accumulation of glutamate during PIDs is strongly curtailed in Ip3r2-deficient mice, resulting in ameliorated calcium overload in neurons and astrocytes. Together, these data implicate astroglial calcium pathways as potential targets for stroke therapy.

Authors

Cordula Rakers, Gabor C. Petzold

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Figure 2

IP3R2-mediated astroglial signaling reduces PID burden without affecting PID-related cerebrovascular changes.

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IP3R2-mediated astroglial signaling reduces PID burden without affecting...
(A–C) Total number of PIDs, latency to first PID, and cumulative AUC as an indicator of overall PID burden were reduced in Ip3r2–/– mice (n = 14) compared with controls (n = 11 mice). (D–G) Infarct volumetry and cell densitometry 72 hours after MCAO revealed a reduced infarct size (n = 15 mice for each group) and a reduced density of dead neurons (quantified by Fluoro-Jade C [FJC]) (n = 15 mice in each group). Arrows in G indicate cortical neurodegeneration. Scale bar: 1 mm (H) Penetrating arterioles showed strong vasoconstriction during PIDs. Left panel shows the vasculature (labeled with Texas Red dextran) during pMCAO before PID; right panel shows the vasculature during PID. Scale bar: 50 μm. (I) Resliced image (indicated by the dashed line in H) used to determine the arteriolar diameter. Scale bar: 5 μm. Spatial measurements of Texas Red fluorescence (lower trace) demonstrate the diameter decrease during the PID. (J and K) The vascular response to PID, consisting of a vasoconstriction followed by a variable vasodilation, remained unchanged in both groups (n = 4 Cx43-ECFP Ip3r2–/– mice; n = 7 control mice). All P values were determined by Mann-Whitney U test.