Microglia-to-astrocyte communication modulates synaptic and cerebrovascular functions following traumatic brain injury

Activation of microglia and astrocytes contributes to synaptic remodeling, tissue repair and neuronal survival following traumatic brain injury (TBI). However, the consequences of the interaction between both glial cell types in rewiring neuronal networks and repairing brain functions remains poorly understood. Here, we explored how microglia-induced astrocyte activation modified synapses and cerebrovascular integrity following TBI. Calcium imaging experiments from brain slices revealed increased number of active astrocytes responding with spontaneous Ca events surrounding the injury at 1 d.a.i. These changes correlated with an increase in astrocytic GFAP-reactivity and microglia activation. Blocking microglia activation with the TLR4-blocker TAK242 reduced both the number of active and reactive astrocytes, suggesting a role for microglia in mediating astrocyte excitability. To determine the physiological consequences of microglia-induced astrocyte activation, we first quantified the number of synaptic puncta in TBI-mice treated with the TLR4-blocker. PSD-95/VGlut-1 staining showed that TAK-treatment reduced by half the synaptic loss observed in TBI-mice. Similar effects were also observed in the blood-brain barrier (BBB) integrity, in which blockage of microglia decreased Evans Blue extravasation, an indicative of preserved BBB. The acute effects of microglia inhibition on synapses and BBB were not observed in IPR2 mice, indicating that the microglial effects depend on the subsequent astrocyte activation. In addition, acute TBI increases the release of the astrocytic-protein thrombospondin-1 (TSP-1) that seems to be necessary to modulate synaptic puncta in a sub-acute phase. Together, our data demonstrate that microglia-to-astrocyte communication plays a crucial role in the pathophysiology of TBI and that its inhibition prevents the synaptic loss and BBB damage accelerating the recovery/repair of damaged tissue. Overall, our data indicates that targeting the microglia-astrocyte crosstalk might represent a therapeutic potential in CNS injuries and disorders.