Microglia Modulate Cortical Spreading Depolarizations After Ischemic Stroke: A Narrative Review

Abstract

Cortical spreading depolarizations (CSDs) are characterized by waves of diminished electroencephalography activity that propagate across the cortex with subsequent loss of ionic homeostasis. CSDs have been found in many pathological conditions, including migraine, traumatic brain injury, and ischemic stroke. Because of CSD-associated ionic and metabolic disturbances at the peri-infarct area after ischemic stroke, it is thought that CSDs exacerbate tissue infarction and worsen clinical outcomes. Microglia, the main innate immune cells in the brain, are among the first responders to brain tissue damage. Recent studies demonstrated that microglia play a critical role in CSD initiation and propagation. In this article, we discuss the significance of CSD in the setting of ischemic stroke and how microglia may modulate peri-infarct CSDs, also known as iso-electric depolarizations. Finally, we discuss the significance of microglial Ca²⁺ and how it might be used as a potential therapeutic target for patients with ischemic stroke.

Keywords: 2-Photon; Calcium signaling; Cortical spreading depolarization; In vivo imaging; Ischemic stroke; Iso-electric depolarizations; Microglia.

Fig. 1

Neuron–microglia interactions in the setting of cortical spreading depolarization (CSD). After ischemic injury, neurons and microglia can engage in a self-propagating feedback loop, potentially worsening stroke outcome. Initial CSDs, occurring during prolonged depolarization of neurons at around − 10 mV, cause increase of extracellular purines, such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine, as well as potassium (K⁺). ATP/ADP activate both ionotropic purinergic receptors, P2X, and metabotropic purinergic receptors, P2Y, on microglia. Activation of P2X channels mediates Ca²⁺ influx in microglia, whereas the activation of P2Y receptors triggers Ca²⁺ release from microglial endoplasmic reticulum (ER) through phospholipase C–inositol 1,4,5-trisphosphate (PLC-IP3) signaling pathways. The depletion of ER store activates the calcium release-activated calcium (CRAC) channels, mediating additional Ca²⁺ influx into microglia. These events converge on the major elevation of intracellular Ca²⁺. High Ca²⁺ levels stimulate the inflammatory cytokine production through the calcineurin–nuclear factor of activated T cells (NFAT) pathway. Cytokines affect the CSD threshold in the nearby neurons by modulating N-methyl-D-aspartate (NMDA) currents. Sustained activation of NMDA receptors (NMDAR) further increases K⁺ leak to the extracellular space, provoking the next CSD initiation and propagation. This positive feedback loop may exacerbate neuronal damage in the periinfarct penumbra after stroke

Fig. 2

Calcium influx as an emerging treatment target for ischemic stroke. Blockade of Ca²⁺ influx through the calcium release-activated calcium (CRAC) channels may be a new therapeutic strategy for the treatment of ischemic stroke. Pharmacological inhibition of the CRAC-mediated Ca²⁺ current in the ischemic brain could facilitate significant benefits, without adverse side effects