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

Abstract Astrocytes 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 Ca 2+ signalling, we now show this form of metaplasticity requires inositol triphosphate receptor-dependent Ca 2+ release in these cells. Blocking Ca 2+ signalling or inositol triphosphate receptors in single radiatum astrocytes abolishes the metaplasticity at nearby synapses. We also show the relevant Ca 2+ release in astrocytes is driven by adenosine A 2B receptors, and stimulation of these receptors elicits the metaplasticity effect both in vitro and in 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 points In hippocampal CA1, “priming” activity inhibits subsequent LTP at synapses hundreds of microns away. This effect requires astrocytic Ca 2+ signaling, and a molecular cascade involving adenosine A 2B receptors, tumor necrosis factor and GluN2B-containing NMDA receptors. The metaplasticity effect is evident in vitro and in vivo . Long-distance astrocyte signaling is a mechanism for regulating neural activity over broad spatiotemporal scales.