Abstract
Astrocytes are abundant cells in the brain that regulate multiple aspects of neural tissue homeostasis by providing structural and metabolic support to neurons, maintaining synaptic environments and regulating blood flow. Recent evidence indicates that astrocytes also actively participate in brain functions and play a key role in brain disease by responding to neuronal activities and brain insults. Astrocytes become reactive in response to injury and inflammation, which is typically described as hypertrophy with increased expression of glial fibrillary acidic protein (GFAP). Reactive astrocytes are frequently found in many neurological disorders and are a hallmark of brain disease. Furthermore, reactive astrocytes may drive the initiation and progression of disease processes. Recent improvements in the methods to visualize the activity of reactive astrocytes in situ and in vivo have helped elucidate their functions. Ca2+ signals in reactive astrocytes are closely related to multiple aspects of disease and can be a good indicator of disease severity/state. In this review, we summarize recent findings concerning reactive astrocyte Ca2+ signals. We discuss the molecular mechanisms underlying aberrant Ca2+ signals in reactive astrocytes and the functional significance of aberrant Ca2+ signals in neurological disorders.
Highlights
Astrocytes constitute approximately 30% of the cells of the brain and occupy non-overlapping spatial domains in the central nervous system
We focus on recent findings made in the last five years and, we do not reference many of the prior studies that are fundamental to our understanding of Ca2+ signaling in astrocytes
In a model of Alexander disease (AxD), a rare neurodegenerative disease caused by autosomal dominant gain of function mutations in glial fibrillary acidic protein (GFAP), we recently found extraordinarily large Ca2+ signals in astrocytes, whose areas were over 300 μm2
Summary
Astrocytes constitute approximately 30% of the cells of the brain and occupy non-overlapping spatial domains in the central nervous system. Bulk-loading of acetoxymethyl (AM) ester forms of indicator dyes is used in many studies because they are easy to load into cells in situ and in vivo and reliably report Ca2+ signals. Most of an astrocyte’s surface area (90–95%) consists of branchlets and leaflets [1] In these fine structures, Ca2+ signals cannot be reliably measured by bulk-loading of a Ca2+ indicator. Dye loading increases extracellular ATP, possibly through dying cells [18] These findings indicate that data obtained using organic Ca2+ indicators should be interpreted with caution. High expression levels of GECIs can cause cellular damage [19] Because of their brightness and photostability, GECIs are suitable for wide-field imaging, revealing global Ca2+ elevation in astrocytes, which occurs synchronously in many astrocytes throughout the cortex [20]. Noradrenaline, derived from locus coeruleus neurons in response to arousal or startle, causes global Ca2+ signals [20,21,22]
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