Local energy on demand: Are 'spontaneous' astrocytic Ca2+-microdomains the regulatory unit for astrocyte-neuron metabolic cooperation?

Abstract

Astrocytes are a neural cell type critically involved in maintaining brain energy homeostasis as well as signaling. Like neurons, astrocytes are a heterogeneous cell population. Cortical astrocytes show a complex morphology with a highly branched aborization and numerous fine processes ensheathing the synapses of neighboring neurons, and typically extend one process connecting to blood vessels. Recent studies employing genetically encoded fluorescent calcium (Ca²⁺) indicators have described 'spontaneous' localized Ca²⁺-transients in the astrocyte periphery that occur asynchronously, independently of signals in other parts of the cells, and that do not involve somatic Ca²⁺ transients; however, neither it is known whether these Ca²⁺-microdomains occur at or near neuronal synapses nor have their molecular basis nor downstream effector(s) been identified. In addition to Ca²⁺ microdomains, sodium (Na⁺) transients occur in astrocyte subdomains, too, most likely as a consequence of Na⁺ co-transport with the neurotransmitter glutamate, which also regulates mitochondrial movements locally - as do cytoplasmic Ca²⁺ levels. In this review, we cover various aspects of these local signaling events and discuss how structural and biophysical properties of astrocytes might foster such compartmentation. Astrocytes metabolically interact with neurons by providing energy substrates to active neurons. As a single astrocyte branch covers hundreds to thousands of synapses, it is tempting to speculate that these metabolic interactions could occur localized to specific subdomains of astrocytes, perhaps even at the level of small groups of synapses. We discuss how astrocytic metabolism might be regulated at this scale and which signals might contribute to its regulation. We speculate that the astrocytic structures that light up transiently as Ca²⁺-microdomains might be the functional units of astrocytes linking signaling and metabolic processes to adapt astrocytic function to local energy demands. The understanding of these local regulatory and metabolic interactions will be fundamental to fully appreciate the complexity of brain energy homeostasis as well as its failure in disease and may shed new light on the controversy about neuron-glia bi-directional signaling at the tripartite synapse.

Keywords: Brain energy metabolism; Calcium microdomain; Functional compartmentation; Peripheral astrocyte process (PAP); Tripartite synapse.