Trends in Neurosciences
Volume 26, Issue 10, October 2003, Pages 536-542
Journal home page for Trends in Neurosciences

New roles for astrocytes: Regulation of synaptic transmission

https://doi.org/10.1016/S0166-2236(03)00237-6Get rights and content

Abstract

Although glia often envelop synapses, they have traditionally been viewed as passive participants in synaptic function. Recent evidence has demonstrated, however, that there is a dynamic two-way communication between glia and neurons at the synapse. Neurotransmitters released from presynaptic neurons evoke Ca2+ concentration increases in adjacent glia. Activated glia, in turn, release transmitters, including glutamate and ATP. These gliotransmitters feed back onto the presynaptic terminal either to enhance or to depress further release of neurotransmitter. Transmitters released from glia can also directly stimulate postsynaptic neurons, producing either excitatory or inhibitory responses. Based on these new findings, glia should be considered an active partner at the synapse, dynamically regulating synaptic transmission.

Section snippets

Neuronal activation of glia

Astrocytes and other CNS glia express a wide variety of neurotransmitter receptors 11, 12. Activation of these receptors evokes a rich repertoire of responses in glia, including increases in intracellular Ca2+ concentration ([Ca2+]) and release of gliotransmitters, including glutamate and ATP.

Glial responses to neurotransmitters were initially characterized in vitro, using cultured astrocytes as a model system. These studies demonstrated that glial [Ca2+] increases could be evoked by a variety

Glutamate release from astrocytes

Glial [Ca2+] increases evoked by neuronal activity might be written off as a curious epiphenomenon of little importance to brain function if it were not for the fact that they initiate additional glial responses. Perhaps the most significant of these Ca2+-dependent responses is the release of glutamate from glia.

In both culture 24, 25, 26, 27 and brain-slice 15, 14, 28, 29 preparations, increases in [Ca2+] result in a release of glutamate from astrocytes. The mechanism by which glutamate is

Modulation of synaptic transmission in culture

Glial regulation of synaptic transmission has been best characterized in co-cultures of astrocytes and neurons, where [Ca2+] increases can be evoked in astrocytes by several stimuli, including electrical and mechanical stimulation and application of peptides and prostaglandin E2 (PGE2) 24, 25, 26, 32, 33. Activation of astrocytes reduces the amplitude of excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs, respectively) evoked by electrical stimulation of presynaptic neurons [25] (

Modulation in brain slices

Recent experiments employing brain slices and other preparations in which the morphological relationship between neurons and glia is preserved also reveal glial regulation of synaptic transmission. In the hippocampus, repetitive firing of inhibitory interneurons leads to potentiation of synaptic transmission between the interneurons and pyramidal cells. This potentiation is mediated by glutamate release from neighboring astrocytes [15]. Potentiation arises when GABA, released from the

Modulation in the retina

Glia can also modulate synaptic activity driven by natural, physiological stimuli. This has been demonstrated in the mammalian retina, where glial activation modulates ganglion cell spike activity that is driven by light stimulation [35]. (Ganglion cells are the output neurons of the retina that project to the brain.) For some ganglion cells, light-evoked spiking is enhanced when neighboring glia are activated; in other ganglion cells, spiking is inhibited (Figure 2c). The precise mechanism of

Modulation at the neuromuscular junction

Glial modulation of synaptic transmission is not limited to the CNS. A dramatic example of such modulation occurs at the neuromuscular junction, where perisynaptic Schwann cells are responsible for half of the synaptic depression seen during repetitive stimulation of the motor nerve 6, 18, 39, 40. Release of ACh and ATP from the presynaptic terminal activates the perisynaptic Schwann cell, evoking a Ca2+-independent release of a gliotransmitter, thought to be glutamate, from the glial cell 6, 18

Other forms of synaptic modulation

As reviewed in preceding sections, release of gliotransmitters from glia can modulate the release of neurotransmitters from the presynaptic terminal and can stimulate postsynaptic neurons. This mechanism of synaptic regulation can be termed ‘direct modulation’. Glia can also regulate synaptic transmission by ‘indirect’ mechanisms.

The best characterized of the indirect regulatory mechanisms is the uptake of glutamate by glia via excitatory amino acid transporters 43, 44. Synaptic transmission at

Concluding remarks

There is increasing evidence that glia play a dynamic role in regulating synaptic transmission. Experiments conducted in both culture and intact-tissue preparations demonstrate that transmitters released from neurons can stimulate glia, leading to the release of glutama4te, ATP and other neuroactive substances from the glia. These gliotransmitters can feed back onto the presynaptic terminal to either enhance or depress the further release of neurotransmitter. Gliotransmitters released from glia

Acknowledgements

My research is supported by NIH grant EY04077 I thank Paul Ceelen for preparation of illustrations and Janice Gepner, Paul Mermelstein and Monica R. Metea for comments on the manuscript.

References (66)

  • J Grosche

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

    Nat. Neurosci.

    (1999)
  • J Grosche

    Bergmann glial cells form distinct morphological structures to interact with cerebellar neurons

    J. Neurosci. Res.

    (2002)
  • E.A Newman

    Chapter 6: Glia of the retina

  • N.E Reist et al.

    Neurally evoked calcium transients in terminal Schwann cells at the neuromuscular junction

    Proc. Natl. Acad. Sci. U. S. A.

    (1992)
  • A Volterra et al.

    Release of transmitters from glial cells

  • A Volterra

    The Tripartite Synapse. Glia in Synaptic Transmission

    (2002)
  • S.M Finkbeiner

    Glial calcium

    Glia

    (1993)
  • J.T Porter et al.

    Hippocampal astrocytes in situ respond to glutamate released from synaptic terminals

    J. Neurosci.

    (1996)
  • L Pasti

    Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ

    J. Neurosci.

    (1997)
  • J Kang

    Astrocyte-mediated potentiation of inhibitory synaptic transmission

    Nat. Neurosci.

    (1998)
  • A Araque

    Synaptically released acetylcholine evokes Ca2+ elevations in astrocytes in hippocampal slices

    J. Neurosci.

    (2002)
  • O.B Paulson et al.

    Does the release of potassium from astrocyte endfeet regulate cerebral blood flow?

    Science

    (1987)
  • M Zonta

    Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation

    Nat. Neurosci.

    (2003)
  • E.A Newman et al.

    Calcium waves in retinal glial cells

    Science

    (1997)
  • E.A Newman

    Propagation of intercellular calcium waves in retinal astrocytes and Müller cells

    J. Neurosci.

    (2001)
  • C.G Schipke

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

    FASEB J.

    (2002)
  • V Parpura

    Glutamate-mediated astrocyte–neuron signalling

    Nature

    (1994)
  • A Araque

    Glutamate-dependent astrocyte modulation of synaptic transmission between cultured hippocampal neurons

    Eur. J. Neurosci.

    (1998)
  • A Araque

    Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons

    J. Neurosci.

    (1998)
  • B Innocenti

    Imaging extracellular waves of glutamate during calcium signaling in cultured astrocytes

    J. Neurosci.

    (2000)
  • P Bezzi

    Prostaglandins stimulate calcium-dependent glutamate release in astrocytes

    Nature

    (1998)
  • L Pasti

    Cytosolic calcium oscillations in astrocytes may regulate exocytotic release of glutamate

    J. Neurosci.

    (2001)
  • A Araque

    SNARE protein-dependent glutamate release from astrocytes

    J. Neurosci.

    (2000)
  • Cited by (0)

    View full text