Astrocytic Ca²⁺ signals are required for the functional integrity of tripartite synapses

Background: Neuronal activity alters calcium ion (Ca²⁺) dynamics in astrocytes, but the physiologic relevance of these changes is controversial. To examine this issue further, we generated an inducible transgenic mouse model in which the expression of an inositol 1,4,5-trisphosphate absorbent, "IP₃ sponge", attenuates astrocytic Ca²⁺ signaling. Results: Attenuated Ca²⁺ activity correlated with reduced astrocytic coverage of asymmetric synapses in the hippocampal CA1 region in these animals. The decreased astrocytic 'protection' of the synapses facilitated glutamate 'spillover', which was reflected by prolonged glutamate transporter currents in stratum radiatum astrocytes and enhanced N-methyl-D-aspartate receptor currents in CA1 pyramidal neurons in response to burst stimulation. These mice also exhibited behavioral impairments in spatial reference memory and remote contextual fear memory, in which hippocampal circuits are involved. Conclusions: Our findings suggest that IP₃-mediated astrocytic Ca²⁺ signaling correlates with the formation of functional tripartite synapses in the hippocampus.