Abstract:
Astrocytes are sensitive to ongoing neuronal/network activities and, accordingly, regulate neuronal functions (synaptic transmission, synaptic plasticity, behavior, etc.) by the context-dependent release of several gliotransmitters (e.g., glutamate, glycine, D-serine, ATP). To sense diverse input, astrocytes express a plethora of G-protein coupled receptors, which couple, via G(i/o) and G(q), to the intracellular Ca(2+) release channel IP(3)-receptor (IP(3)R). Indeed, manipulating astrocytic IP(3)R-Ca(2+) signaling is highly consequential at the network and behavioral level: Depleting IP(3)R subtype 2 (IP(3)R2) results in reduced GPCR-Ca(2+) signaling and impaired synaptic plasticity; enhancing IP(3)R-Ca(2+) signaling affects cognitive functions such as learning and memory, sleep, and mood. However, as a result of discrepancies in the literature, the role of GPCR-IP(3)R-Ca(2+) signaling, especially under physiological conditions, remains inconclusive. One primary reason for this could be that IP(3)R2 has been used to represent all astrocytic IP(3)Rs, including IP(3)R1 and IP(3)R3. Indeed, IP(3)R1 and IP(3)R3 are unique Ca(2+) channels in their own right; they have unique biophysical properties, often display distinct distribution, and are differentially regulated. As a result, they mediate different physiological roles to IP(3)R2. Thus, these additional channels promise to enrich the diversity of spatiotemporal Ca(2+) dynamics and provide unique opportunities for integrating neuronal input and modulating astrocyte-neuron communication. The current review weighs evidence supporting the existence of multiple astrocytic-IP(3)R isoforms, summarizes distinct sub-type specific properties that shape spatiotemporal Ca(2+) dynamics. We also discuss existing experimental tools and future refinements to better recapitulate the endogenous activities of each IP(3)R isoform.

Abstract:
An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Abstract:
Astrocytic Ca(2+) signals can be fast and local, supporting the idea that astrocytes have the ability to regulate single synapses. However, the anatomical basis of such specific signaling remains unclear, owing to difficulties in resolving the spongiform domain of astrocytes where most tripartite synapses are located. Using 3D-STED microscopy in living organotypic brain slices, we imaged the spongiform domain of astrocytes and observed a reticular meshwork of nodes and shafts that often formed loop-like structures. These anatomical features were also observed in acute hippocampal slices and in barrel cortex in vivo. The majority of dendritic spines were contacted by nodes and their sizes were correlated. FRAP experiments and Ca(2+) imaging showed that nodes were biochemical compartments and Ca(2+) microdomains. Mapping astrocytic Ca(2+) signals onto STED images of nodes and dendritic spines showed they were associated with individual synapses. Here, we report on the nanoscale organization of astrocytes, identifying nodes as a functional astrocytic component of tripartite synapses that may enable synapse-specific communication between neurons and astrocytes.