Foundations and implications of astrocyte heterogeneity during brain development and disease

Astrocytes have complex roles in brain circuit formation and physiology. Recent studies have revealed that astrocytes display heterogeneous molecular, morphological, and functional signatures between and within brain regions. Patterning and specification of glial progenitors play an early role in creating heterogenous astrocytic subpopulations, upon which subsequent signaling events elicited through extrinsic factors enable the full diversity of astrocytes to be reached. The processes of astrocyte maturation and synaptogenesis are interlinked in time and space, enabling astrocytes to influence synapse formation, function, and elimination and neurons to regulate astrocytic properties. The astrocytic responses to aging, inflammation, and disease states are heterogeneous and can differentially alter synaptic function and pathological outcomes. Astrocytes play crucial roles in regulating brain circuit formation and physiology. Recent technological advances have revealed unprecedented levels of astrocyte diversity encompassing molecular, morphological, and functional differences. This diversification is initiated during embryonic specification events and (in rodents) continues into the early postnatal period where it overlaps with peak synapse development and circuit refinement. In fact, several lines of evidence suggest astrocyte diversity both influences and is a consequence of molecular crosstalk among developing astrocytes and other cell types, notably neurons and their synapses. Neurological disease states exhibit additional layers of astrocyte heterogeneity, which could help shed light on these cells' key pathological roles. This review highlights recent advances in clarifying astrocyte heterogeneity and molecular/cellular crosstalk and identifies key outstanding questions. Astrocytes play crucial roles in regulating brain circuit formation and physiology. Recent technological advances have revealed unprecedented levels of astrocyte diversity encompassing molecular, morphological, and functional differences. This diversification is initiated during embryonic specification events and (in rodents) continues into the early postnatal period where it overlaps with peak synapse development and circuit refinement. In fact, several lines of evidence suggest astrocyte diversity both influences and is a consequence of molecular crosstalk among developing astrocytes and other cell types, notably neurons and their synapses. Neurological disease states exhibit additional layers of astrocyte heterogeneity, which could help shed light on these cells' key pathological roles. This review highlights recent advances in clarifying astrocyte heterogeneity and molecular/cellular crosstalk and identifies key outstanding questions.