Astrocyte heterogeneity: an underappreciated topic in neurobiology

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Astrocytes, one of the most numerous types of cells in the central nervous system, are crucial for potassium homeostasis, neurotransmitter uptake, synapse formation, regulation of blood–brain-barrier, and the development of the nervous system. Historically, astrocytes have been studied as a homogeneous group of cells. However, evidence has accumulated that suggests heterogeneity of astrocytes across brain regions as well as within the same brain regions. Astrocytes differ in their morphology, developmental origin, gene expression profile, physiological properties, function, and response to injury and disease. A better understanding of the heterogeneity of astrocytes will greatly aid investigation of the function of astrocytes in normal brain as well as the roles of astrocytes in neurological disorders.

Section snippets

Developmental heterogeneity

Different types of neurons originate from distinct progenitors. For example, cortical projection neurons originate from progenitors in the embryonic ventricular zone and they migrate radially to their final location. By contrast, cortical GABAergic interneurons arise from progenitors in the embryonic subpallium region and migrate tangentially to the cortex [9]. Astrocytes are found throughout the central nervous system. Do they arise from the same pool of progenitors or distinct groups of

Gene expression heterogeneity

Extensive evidence showed that astrocytes are highly heterogeneous with regard to their gene expression profiles. Using a novel translational profiling approach called translating ribosome affinity purification (TRAP), Heintz and colleagues compared translated mRNAs in cortical astrocytes, cerebellar astrocytes, and cerebellar Bergman glia, and reported substantial differences in gene expression between astrocytes from different brain regions [23••]. A recent microarray analysis of cultured

Physiological heterogeneity

Astrocytes have been traditionally described as a uniform group of cells with negative resting membrane potential, low input resistance, and extensive gap junction coupling. Recent studies indicate that astrocytes are highly diverse in their electrophysiological properties, calcium dynamics, and gap junction coupling.

The resting membrane potential of astrocytes varies widely, ranging from about −85 to −25 mV in acute hippocampal slices [47] and isolated optic nerves [48]. The distribution of

Functional heterogeneity

Astrocytes carry out a number of important functions including regulating extracellular concentrations of potassium ion and neurotransmitters, promoting synapse formation, regulating blood–brain-barrier, promoting neuronal survival and growth, producing neurons, and perhaps modulating synaptic transmission and plasticity. The effects of astrocytes on synaptic transmission are highly controversial. A number of studies employing a variety of pharmacological, optical, and genetic methods suggest

Heterogeneous response to injury and disease

Astrocytes respond to various injuries, infections, and diseases by reactive astrogliosis, which has both detrimental effects, for example, scar formation that prevents regrowth of injured axon and beneficial effects, for example, sealing the blood brain barrier. Astrocytes in epileptic brain both promote and oppose seizure development through a variety of mechanisms. Astrocytes play a key role in the pathogenesis of hepatic encephalopathy. Damage to astrocytes is seen in neurodegenerative

Conclusions

Astrocytes are a far more heterogeneous group of cells than was previously appreciated. Different subtypes of astrocytes differ in morphology, development, metabolism, physiology, and pathology. However, our current understanding of astrocyte heterogeneity, in particular the functional heterogeneity of astrocytes is still rudimentary. A large number of studies mentioned above are based on observations from cultured astrocytes in vitro. Improved culture methods that faithfully maintain in vivo

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors apologize to colleagues whose work was not included because of the space restrictions.

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