Combined molecular and functional analyses have revealed that astrocytes are direct, active communication partners of neurons. They comprise a heterogeneous group of cells that are distinguished by their morphology, molecular assembly, functional characteristics and regional distribution within the CNS. Defective astrocytes are involved in various neurological disorders. Dysfunction of glial glutamate transporters seems to represent a spanning phenomenon common to many pathological conditions.
The hippocampus of patients with temporal lobe epilepsy shows severe histopathological abnormalities. Recent studies showed that in the sclerotic hippocampus dislocation of water channels (aquaporin 4; AQP4) and reduced expression of inwardly rectifying K+ (Kir) channels in astrocytes could contribute to impaired K+ buffering and increased seizure propensity. Moreover, dysregulation of glial glutamate uptake, slowed glutamate–glutamine cycling and subsequent extracellular transmitter accumulation seem to contribute to seizure generation in hippocampal sclerosis.
Astrocytes contribute to the pathology of sporadic amyotrophic lateral sclerosis (ALS). Dysfunction of glial glutamate transporters causes increases in extracellular glutamate concentrations and excitotoxic neuronal damage. In hereditary forms of ALS, mutations of Cu/Zn superoxide dismutase (SOD1) lead to oxidative stress and aberrant biochemistry in motor neurons and astrocytes. Apparently, fatal dysregulation of neuron–glia interactions leads to neurotoxicity through the release of reactive oxygen species, prostaglandins, mutant SOD1 and neurotransmitters.
The realization that several membrane proteins are highly segregated in astrocytes, with AQP4 and Kir channels being prominent examples, provides a molecular basis to view astrocytes as fundamental regulators of neurovascular units. Redistribution and functional impairment of these molecules, which is seen following ischaemia and stroke, suggests that they represent potential targets for therapeutic interventions. Moreover, astrocytes are becoming increasingly recognized as the source of a plethora of regulatory molecules that influence neurogenesis, neuritogenesis and vasculogenesis, and, as such, could function as orchestrators of these processes in development and regeneration.
Hepatic insufficiency leads to hyperammonaemia and elevated concentrations of ammonia in cerebrospinal fluid. Enhanced uptake of ammonia/ammonium ions by astrocytes affects the glutamate–glutamine cycle, resulting in swelling, perturbed K+ homeostasis and reduced glutamate uptake. Although the role of astrocytes in hepatic encephalopathy has been well studied, a useful molecular target to prevent their dysfunction has not yet been identified.
Although a vast body of evidence documents astroglial dysfunction and dysregulation of astroglia-specific functions in various diseases, it seems premature to try to construe a unifying picture from these data. In particular, it is still often unclear whether glial changes are causative of a given disease or represent an accompanying phenomenon. A better definition of astroglial subtypes should promote our understanding of their specific roles in pathophysiology and the development of cell-centred therapeutic approaches.
Recent work on glial cell physiology has revealed that glial cells, and astrocytes in particular, are much more actively involved in brain information processing than previously thought. This finding has stimulated the view that the active brain should no longer be regarded solely as a network of neuronal contacts, but instead as a circuit of integrated, interactive neurons and glial cells. Consequently, glial cells could also have as yet unexpected roles in the diseased brain. An improved understanding of astrocyte biology and heterogeneity and the involvement of these cells in pathogenesis offers the potential for developing novel strategies to treat neurological disorders.
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The authors wish to thank D. Binder for comments on the manuscript. Work of the authors is supported by Deutsche Forschungsgemeinschaft. We apologize to all those whose work could not be discussed due to space constraints.
The authors declare no competing financial interests.
- Complex glial cells
Cells in the postnatal brain that express various types of voltage- and time-dependent ion channels as well as transmitter receptors. They do not generate action potentials and have been shown to express S100β.
- GluR-type glial cells
Cells in the postnatal hippocampus that express voltage- and time-dependent ion channels and glutamate receptors of the AMPA type. These cells receive synaptic input from glutamatergic and GABA-containing neurons, and lack gap junctional coupling as well as functional glutamate transporters. They express glial fibrillary acidic protein transcripts and S100β protein and probably represent a subpopulation of the complex glial cells.
- Gap junctions
Gap junctions are channels composed of two juxtaposed hexameric hemichannels (connexons) forming intercellular pathways for the diffusion of ions and small molecules.
- Inwardly rectifying K+ channels
(Kir channels). These comprise a large family of transmembrane proteins that allow preferred passage of K+ at negative membrane potentials.
- Müller glia
A radial-shaped type of astroglial cell that spans the entire thickness of the retina and tightly envelops retinal neurons and neuronal processes. It constitutes the majority of retinal astroglia and is central to retinal development and function.
- Ammon's horn sclerosis
(AHS). A histopathological condition often associated with temporal lobe epilepsy, characterized by selective neuronal cell loss in the CA1 and CA4 regions of the hippocampus and reactive sclerosis.
Tissue damage in the CNS resulting from a lack of adequate blood supply. Stroke is a major cause of death and permanent disability.
- Neurovascular unit
Describes a dynamic ensemble comprising neurons, astroglial cells, vascular endothelia, and their associated extracellular matrices. The neurovascular unit is viewed as a modular unit integrating CNS function and perfusion (blood supply).
- Volume-sensitive osmolyte and anion channel
(VSOAC; also known as VRAC). A molecularly so far undefined channel that, on cell swelling, results in an outward rectifying, electrogenic flow of Cl- and mediates a passive efflux of osmolytes.
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Seifert, G., Schilling, K. & Steinhäuser, C. Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci 7, 194–206 (2006). https://doi.org/10.1038/nrn1870
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