Trends in Neurosciences
Volume 26, Issue 10, October 2003, Pages 523-530
Journal home page for Trends in Neurosciences

New roles for astrocytes: Redefining the functional architecture of the brain

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Abstract

Astrocytes have traditionally been considered ancillary, satellite cells of the nervous system. However, work over the past decade has revealed that they interact with the vasculature to form a gliovascular network that might organize not only the structural architecture of the brain but also its communication pathways, activation, thresholds and plasticity. The net effect is that astroglia demarcate gray matter regions, both cortical and subcortical, into functional compartments whose internal activation thresholds and external outputs are regulated by single glial cells. The array of these astrocyte-delimited microdomains along the capillary microvasculature allows the formation of higher-order gliovascular units, which serve to match local neural activity and blood flow while regulating neuronal firing thresholds through coordinative glial signaling. By these means, astrocytes might establish the functional as well as the structural architecture of the adult brain.

Section snippets

The phylogenetic advance of the astrocyte

The relative number of astrocytes, expressed both as a proportion of total brain cell number and as a ratio to neuronal number, increases with dramatically with phylogeny and brain complexity. In the leech, a typical ganglion is composed of 25–30 neurons and only one astrocyte (Figure 1). In Caenorhabditis elegans, neurons outnumber glia by 6:1 [2], whereas astrocytes and neurons are represented in a ratio of 1:3 in the cortex of lower mammals such as rats and mice. In the human cortex, there

Astrocytes establish non-overlapping territories that define functional domains

Astrocytes typically extend between five and eight major processes, each of which ramifies into fine and essentially uniformly distributed leaflet-like appendages [11]. Unexpectedly, the elaborate and dense processes of each hippocampal astrocyte define a 3D space that is free of processes from any other astrocytes. In this way, the astrocyte defines its own anatomical domain. Only the most peripheral processes interdigitate with one another, doing so along a narrow interface within which <5%

Signal propagation among astrocytes

Having learned from neurons by classical electrophysiological methods, these same methods were eagerly applied to astrocytes. The results were somewhat boring. Astrocytes are electrically non-excitable and they respond to current injection with only passive changes in membrane potential. Their resting membrane potential is maintained at ∼ −85 mV and displays little fluctuation in response to a wide variety of stimuli 4, 18. This stability and their low input resistance is likely to reflect the

Normal and pathological manifestations of glial Ca2+ signaling in vivo

Astrocytic Ca2+ waves are mediated primarily by release of ATP and activation of purine receptors (Box 1). In cultured astrocytes, Ca2+ waves are routinely generated by electrical or mechanical stimulation, but they can also be initiated by exposure to transmitters or by removal of extracellular Ca2+. In addition, recent studies have used confocal imaging to demonstrate that astrocytes in situ can propagate long-distance Ca2+ waves. However, Ca2+ waves in slices can be generated only by intense

Transmitter release by astrocytes

One of the principal functions of astrocytes is uptake of neurotransmitters released from nerve terminals [41]. But astrocytes can also release neuroactive agents, including transmitters, eicosanoids, steroids, neuropeptides and growth factors [42]. The regulation and mechanism (or mechanisms) of astrocyte-mediated release of neuroactive compounds are for most agents poorly defined. They are also hotly debated, given their theoretical importance in brain function. Release of glutamate appears

Interactions among astrocytes, neurons and endothelial cells define the gliovascular unit

The blood–brain barrier is a diffusion barrier that impedes exchange of molecules between the two tissues. The primary seal of the blood–brain barrier is formed by endothelial tight junctions. Astrocytes enwrap the vasculature with a large number of endfeet plastered at the vessel wall (Figure 4), although their role in the blood–brain barrier is poorly defined and they are not believed to have a barrier function in the mammalian brain [49]. Several factors released by astrocytes might be

Concluding remarks

Ideas about glial function originally sprang from the anatomy of these cells. Modern researchers have gained knowledge about glial cells by studying their physiology and biochemistry in isolation from their normal cellular partners. This was necessary to avoid the confounding complexity of the intact CNS. The risk, however, is that we lose sight of the in vivo anatomical relationships of these cells, which define what their sphere of influence can be. Current evidence indicates that anatomy and

Acknowledgements

We thank Marisa Cotrina and Greg Arcuino for discussions, and Marie Simard, Takahiro Takano and Xiaohai Wang for the data illustrated in Figure 1, Figure 2, Figure 3, Figure 4. Our studies are supported by NINDS/NIH, the Brain Tumor Association, and New York State Spinal Cord Injury Research Program.

References (68)

  • J. Kang

    Astrocyte-mediated potentiation of inhibitory synaptic transmission

    Nat. Neurosci.

    (1998)
  • P.G. Haydon

    Glia: listening and talking to the synapse

    Nat. Rev. Neurosci.

    (2001)
  • Newman, E.A. New roles for astrocytes: regulation of synaptic function. Trends Neurosci. (in...
  • F.W. Pfrieger et al.

    Synaptic efficacy enhanced by glial cells in vitro

    Science

    (1997)
  • E.M. Ullian

    Control of synapse number by glia

    Science

    (2001)
  • H. Song

    Astroglia induce neurogenesis from adult neural stem cells

    Nature

    (2002)
  • Horner, P. and Palmer, T. New roles for astrocytes: La vida loca! The nightlife of an astrocyte. Trends Neurosci. (in...
  • E.A. Bushong

    Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains

    J. Neurosci.

    (2002)
  • T. Chan-Ling et al.

    Factors determining the shape, spacing and distribution of astrocytes in the cat retina: The contact-spacing model of astrocyte interaction

    J. Comp. Neurol.

    (1991)
  • Simard, M. et al. Signaling at the gliovascular interface. J. Neurosci. (in...
  • A. Rohlmann et al.

    Subcellular Topography and Plasticity of Gap Junction Distribution on Astrocytes

    (1996)
  • C. Rose et al.

    Gap junctions equalize intracellular Na+ concentrations in astrocytes

    Glia

    (1997)
  • J. Grosche

    Microdomains for neuron–glia interaction: parallel fiber signaling to Bergmann glial cells

    Nat. Neurosci.

    (1999)
  • J. Kang et al.

    Imaging Astrocytes in Acute Brain Slices

    (1999)
  • B.R. Ransom et al.

    The neurophysiology of glial cells

    J. Clin. Neurophysiol.

    (1992)
  • A.H. Cornell-Bell

    Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling

    Science

    (1990)
  • M.J. Berridge

    Calcium – a life and death signal

    Nature

    (1998)
  • R.E. Westenbroek

    Upregulation of L-type Ca2+ channels in reactive astrocytes after brain injury, hypomyelination, and ischemia

    J. Neurosci.

    (1998)
  • A. Verkhratsky

    Glial calcium: homeostasis and signaling function

    Physiol. Rev.

    (1998)
  • D.E. Bergles et al.

    Glial contribution to glutamate uptake at Schaffer collateral–commissural synapses in the hippocampus

    J. Neurosci.

    (1998)
  • A.H. Cornell-Bell

    Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling

    Science

    (1990)
  • C.G. Schipke

    Astrocyte Ca2+ waves trigger responses in microglial cells in brain slices

    FASEB J.

    (2002)
  • J.W. Dani et al.

    The triggering of astrocytic calcium waves by NMDA-induced neuronal activation

    Ciba Found. Symp.

    (1995)
  • H.R. Parri

    Spontaneous astrocytic Ca2+ oscillations in situ drive NMDAR-mediated neuronal excitation

    Nat. Neurosci.

    (2001)
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