Astrocytes can control basal synaptic strength and arteriole tone via their resting Ca²⁺ activity. However, whether resting astrocyte Ca²⁺ can adjust to a new steady-state level, with an impact on surrounding brain cells, remains unknown. Using two-photon Ca²⁺ imaging in male rat acute brain slices of the somatosensory neocortex, we found that theta burst neural activity produced an unexpected long-lasting reduction in astrocyte free Ca²⁺ in the soma and endfeet. The drop in intracellular Ca²⁺ was attenuated by antagonists targeting multiple ionotropic and metabotropic glutamate receptors, and intracellular cascades involved Ca²⁺ stores and nitric oxide. The reduction in astrocyte endfoot Ca²⁺ was coincident with an increase in arteriole tone, and both the Ca²⁺ drop and the tone change were prevented by an NMDA receptor antagonist. Astrocyte patch-clamp experiments verified that the glutamate receptors in question were located on astrocytes and that Ca²⁺ changes within astrocytes were responsible for the long-lasting change in arteriole diameter caused by theta burst neural activity. In astrocytes from animals that lived in an enriched environment, we measured a relatively lower resting Ca²⁺ level that occluded any further drop in Ca²⁺ in response to theta burst activity. These data suggest that electrically evoked patterns of neural activity or natural experience can adjust steady-state resting astrocyte Ca²⁺ and that the effect has an impact on basal arteriole diameter.SIGNIFICANCE STATEMENT The field of astrocyte-neuron and astrocyte-arteriole interactions is currently in a state of refinement. Experimental evidence ex vivo suggests that direct manipulation of astrocyte-free Ca²⁺ regulates synaptic signaling and local blood flow control; however, in vivo experiments fail to link synaptically evoked astrocyte Ca²⁺ transients and immediate changes to various astrocyte-mediated processes. To clarify this discrepancy, we examined a different aspect of astrocyte Ca²⁺: the resting, steady-state free Ca²⁺ of astrocytes, its modulation, and its potential role in the tonic regulation of surrounding brain cells. We found that ex vivo or in vivo neural activity induced a long-lasting reduction in resting free astrocyte Ca²⁺ and that this phenomenon changed arteriole tone.

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