Stroke subtype-dependent synapse elimination by reactive gliosis in mice

Abstract

The pathological role of reactive gliosis in CNS repair remains controversial. In this study, using murine ischemic and hemorrhagic stroke models, we demonstrated that microglia/macrophages and astrocytes are differentially involved in engulfing synapses in the reactive gliosis region. By specifically deleting MEGF10 and MERTK phagocytic receptors, we determined that inhibiting phagocytosis of microglia/macrophages or astrocytes in ischemic stroke improved neurobehavioral outcomes and attenuated brain damage. In hemorrhagic stroke, inhibiting phagocytosis of microglia/macrophages but not astrocytes improved neurobehavioral outcomes. Single-cell RNA sequencing revealed that phagocytosis related biological processes and pathways were downregulated in astrocytes of the hemorrhagic brain compared to the ischemic brain. Together, these findings suggest that reactive microgliosis and astrogliosis play individual roles in mediating synapse engulfment in pathologically distinct murine stroke models and preventing this process could rescue synapse loss.

Neuronal Loss after Stroke Due to Microglial Phagocytosis of Stressed Neurons

“…Blocking the phagocytic receptors MerTK and the vitronectin receptors (integrins α v β 3 or α v β 5 ) can also prevent the phagocytosis of stressed neurons in stroke models [23,43]. Recently it was shown that the knockout of the phagocytic receptor MerTK, specifically in microglia and macrophages, reduced synaptic loss, brain atrophy and neurological deficits in mouse models of both ischemic and hemorrhagic stroke, whereas the knockout of the phagocytic receptor MEGF10, specifically in astrocytes, reduced synaptic loss and brain atrophy only in the ischemic model of stroke [65]. The latter finding suggests that phagocytosis by both microglia and astrocytes can be detrimental in ischemic stroke.…”

Different paradigms of transcranial electrical stimulation improve motor function impairment and striatum tissue injuries in the collagenase-induced intracerebral hemorrhage rat model

“…ICH treatment with tES for one week could not significantly decrease these cells, although tRNS exerted a better effect. Nevertheless, the positive or negative role of gliosis in CNS repair remains to be elucidated [ 61 ].…”

The Specific Role of Reactive Astrocytes in Stroke

“…These two periods coincide with the peak of cerebral edema ( Manley et al, 2000 ). Moreover, AQP4 loss in mice can reduce astrocytes swelling and brain edema and improve neurological recovery after ischemia stroke ( Shi X. et al, 2021 ).…”

“…Phagocytic astrocytes can engulf synaptic components marked by presynaptic and postsynaptic proteins. Inhibition of this pathway can reduce the phagocytosis of astrocytes, improve neurobehavioral outcomes and alleviate brain injury ( Schilling et al, 2005 ; Morizawa et al, 2017 ; Shi X. et al, 2021 ).…”