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Department of Pharmacology, University of Vermont, Burlington, VT 05405

Correspondence to Mark T. Nelson: Mark.Nelson{at}uvm.edu

Active neurons communicate to intracerebral arterioles in part through an elevation of cytosolic Ca²⁺ concentration ([Ca²⁺]_i) in astrocytes, leading to the generation of vasoactive signals involved in neurovascular coupling. In particular, [Ca²⁺]_i increases in astrocytic processes ("endfeet"), which encase cerebral arterioles, have been shown to result in vasodilation of arterioles in vivo. However, the spatial and temporal properties of endfoot [Ca²⁺]_i signals have not been characterized, and information regarding the mechanism by which these signals arise is lacking. [Ca²⁺]_i signaling in astrocytic endfeet was measured with high spatiotemporal resolution in cortical brain slices, using a fluorescent Ca²⁺ indicator and confocal microscopy. Increases in endfoot [Ca²⁺]_i preceded vasodilation of arterioles within cortical slices, as detected by simultaneous measurement of endfoot [Ca²⁺]_i and vascular diameter. Neuronal activity–evoked elevation of endfoot [Ca²⁺]_i was reduced by inhibition of inositol 1,4,5-trisphosphate (InsP₃) receptor Ca²⁺ release channels and almost completely abolished by inhibition of endoplasmic reticulum Ca²⁺ uptake. To probe the Ca²⁺ release mechanisms present within endfeet, spatially restricted flash photolysis of caged InsP₃ was utilized to liberate InsP₃ directly within endfeet. This maneuver generated large amplitude [Ca²⁺]_i increases within endfeet that were spatially restricted to this region of the astrocyte. These InsP₃-induced [Ca²⁺]_i increases were sensitive to depletion of the intracellular Ca²⁺ store, but not to ryanodine, suggesting that Ca²⁺-induced Ca²⁺ release from ryanodine receptors does not contribute to the generation of endfoot [Ca²⁺]_i signals. Neuronally evoked increases in astrocytic [Ca²⁺]_i propagated through perivascular astrocytic processes and endfeet as multiple, distinct [Ca²⁺]_i waves and exhibited a high degree of spatial heterogeneity. Regenerative Ca²⁺ release processes within the endfeet were evident, as were localized regions of Ca²⁺ release, and treatment of slices with the vasoactive neuropeptides somatostatin and vasoactive intestinal peptide was capable of inducing endfoot [Ca²⁺]_i increases, suggesting the potential for signaling between local interneurons and astrocytic endfeet in the cortex. Furthermore, photorelease of InsP₃ within individual endfeet resulted in a local vasodilation of adjacent arterioles, supporting the concept that astrocytic endfeet function as local "vasoregulatory units" by translating information from active neurons into complex InsP₃-mediated Ca²⁺ release signals that modulate arteriolar diameter.

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