Trends in Neurosciences
New roles for astrocytes: Regulation of 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)
Modulation of synaptic efficacy and synaptic depression by glial cells at the frog neuromuscular junction
Neuron
(1998)Tripartite synapses: glia, the unacknowledged partner
Trends Neurosci.
(1999)- et al.
Astrocytic neurotransmitter receptors in situ and in vivo
Prog. Neurobiol.
(1997) Nitric oxide signals parallel fiber activity to Bergmann glial cells in the mouse cerebellar slice
Mol. Cell. Neurosci.
(2001)Transmitter release increases intracellular calcium in perisynaptic Schwann cells in situ
Neuron
(1992)Clearance of glutamate inside the synapse and beyond
Curr. Opin. Neurobiol.
(1999)Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate
Neuron
(1996)- et al.
Modulation of pH by neuronal activity
Trends Neurosci.
(1992) - et al.
Three-dimensional relationships between hippocampal synapses and astrocytes
J. Neurosci.
(1999) - et al.
Quantitative fine-structural analysis of olfactory cortical synapses
Proc. Natl. Acad. Sci. U. S. A.
(1999)
Microdomains for neuron–glia interaction: parallel fiber signaling to Bergmann glial cells
Nat. Neurosci.
Bergmann glial cells form distinct morphological structures to interact with cerebellar neurons
J. Neurosci. Res.
Chapter 6: Glia of the retina
Neurally evoked calcium transients in terminal Schwann cells at the neuromuscular junction
Proc. Natl. Acad. Sci. U. S. A.
Release of transmitters from glial cells
The Tripartite Synapse. Glia in Synaptic Transmission
Glial calcium
Glia
Hippocampal astrocytes in situ respond to glutamate released from synaptic terminals
J. Neurosci.
Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ
J. Neurosci.
Astrocyte-mediated potentiation of inhibitory synaptic transmission
Nat. Neurosci.
Synaptically released acetylcholine evokes Ca2+ elevations in astrocytes in hippocampal slices
J. Neurosci.
Does the release of potassium from astrocyte endfeet regulate cerebral blood flow?
Science
Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation
Nat. Neurosci.
Calcium waves in retinal glial cells
Science
Propagation of intercellular calcium waves in retinal astrocytes and Müller cells
J. Neurosci.
Astrocyte Ca2+ waves trigger responses in microglial cells in brain slices
FASEB J.
Glutamate-mediated astrocyte–neuron signalling
Nature
Glutamate-dependent astrocyte modulation of synaptic transmission between cultured hippocampal neurons
Eur. J. Neurosci.
Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons
J. Neurosci.
Imaging extracellular waves of glutamate during calcium signaling in cultured astrocytes
J. Neurosci.
Prostaglandins stimulate calcium-dependent glutamate release in astrocytes
Nature
Cytosolic calcium oscillations in astrocytes may regulate exocytotic release of glutamate
J. Neurosci.
SNARE protein-dependent glutamate release from astrocytes
J. Neurosci.
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