Astrocyte Ca2+signalling mediates long-distance metaplasticity in the hippocampal CA1

Abstract

AbstractAstrocytes play an increasingly recognised role in regulating synaptic plasticity, but their contribution to metaplasticity is poorly understood. We have previously described a long-distance form of metaplasticity whereby priming stimulation in stratum oriens inhibits subsequent LTP in the neighbouring stratum radiatum of the hippocampal CA1 region of both rats and mice. Using genetic and pharmacological strategies to manipulate astrocytic Ca2+signalling, we now show this form of metaplasticity requires inositol triphosphate receptor-dependent Ca2+release in these cells. Blocking Ca2+signalling or inositol triphosphate receptors in single radiatum astrocytes abolishes the metaplasticity at nearby synapses. We also show the relevant Ca2+release in astrocytes is driven by adenosine A2Breceptors, and stimulation of these receptors elicits the metaplasticity effect bothin vitroandin vivo. Further, the metaplasticity requires signalling via tumor necrosis factor, but this cytokine is required to act on astrocytes, not neurons. Instead, glutamate, acting on GluN2B-containing NMDA receptors, is the likely gliotransmitter that signals to neurons to inhibit LTP. Together these data reveal a novel role for astrocytes in hippocampal LTP regulation across broader spatiotemporal scales than previously recognised.Main pointsIn hippocampal CA1, “priming” activity inhibits subsequent LTP at synapses hundreds of microns away.This effect requires astrocytic Ca2+signaling, and a molecular cascade involving adenosine A2Breceptors, tumor necrosis factor and GluN2B-containing NMDA receptors.The metaplasticity effect is evidentin vitroandin vivo.Long-distance astrocyte signaling is a mechanism for regulating neural activity over broad spatiotemporal scales.