Neuroscience Forefront ReviewDiversity and Specificity of Astrocyte–neuron Communication
Introduction
Astrocytes are recognized as key supportive elements in neuronal function, providing structural and metabolic support for neurons, and controlling brain homeostasis mechanisms. Historically, they were ignored as being active players in cellular processes underlying brain function. This was likely because nervous system function at the time was known to rely on electrical signals, but astrocytes, unlike neurons, are not electrically excitable cells. However, the advent of calcium imaging techniques in the 1990s, which allowed for monitoring changes in cytosolic calcium, challenged the long-held view that neurons are the only active players in brain communication by demonstrating that astrocytes display a form of excitability based on intracellular calcium variations (Cornell-Bell et al., 1990, Charles et al., 1991, Dani et al., 1992, Porter and McCarthy, 1996, Pasti et al., 1997). This cellular excitability can be manifested as intrinsic spontaneous events, and more importantly, as physiological responses to neurotransmitters, neuromodulators, and extracellular changes in environmental conditions. The seminal studies using cultured astrocytes have been expanded in the last two decades in more intact preparations and in vivo to show that calcium-based excitability of astrocytes is a ubiquitous phenomenon in the nervous system (Araque et al., 2014, Rusakov et al., 2014, Volterra et al., 2014, Khakh and Sofroniew, 2015).
Since those early discoveries, researchers have investigated the many types of stimuli that activate astrocytes, the nature of the resultant calcium changes, and the consequence of such astrocyte activation on neuronal and synaptic activity. The fundamental properties and consequences of neuron-astrocyte communication have been extensively described and discussed in a large number of reviews (Hamilton and Attwell, 2010, Min et al., 2012, Araque et al., 2014, Rusakov et al., 2014, Volterra et al., 2014, Khakh and Sofroniew, 2015, De Pitta et al., 2016, Shigetomi et al., 2016, Guerra-Gomes et al., 2017, Savtchouk and Volterra, 2018). In this review, we will focus on paradigmatic examples that reveal a synapse-, cell-, and circuit-specific diversity of the properties and consequences of neuron-astrocyte signaling.
Section snippets
Diversity of astrocyte responses to synaptic transmission
Astrocytes express a plethora of channels, transporters, and receptors that provide a variety of homeostatic and synaptic functions. Notably, astrocytes can express many of the same neurotransmitter receptors expressed by neurons. Consequently, it is not surprising that astrocytes have been shown to be able to respond to a wide variety of neurotransmitters. Most of the original studies using cultured cells and pharmacological assays to test the astrocyte responsiveness to different
Diversity of mechanisms underlying gliotransmitter release
Astrocytes are known to influence synaptic transmission via a variety of mechanisms. Historically, astrocytes were thought to only play a passive, homeostatic role in influencing synaptic transmission, through, for example, potassium buffering and transmitter clearance (Hertz, 1965, Chaudhry et al., 1995, Higashi et al., 2001, Lehre and Rusakov, 2002, Witcher et al., 2007, Xin and Bonci, 2018). Within the last few decades, however, astrocytes have been shown to play a more active role via the
Diversity of synaptic effects of gliotransmitters
Numerous studies have found that astrocytes can release a variety of signaling molecules, such as glutamate, D-serine, ATP/adenosine, and GABA (Min et al., 2012, Araque et al., 2014, De Pitta et al., 2016, Guerra-Gomes et al., 2017, Savtchouk and Volterra, 2018). The effect of each gliotransmitter on synaptic communication depends on the specific neuronal environment. For instance, the release of just one gliotransmitter (e.g. glutamate) can have both inhibitory (Andersson et al., 2007) or
Concluding remarks
As discussed above, astrocyte–neuron signaling is a complex phenomenon that encompasses great diversity in the mechanisms and functional consequences on network function (Fig. 1). There is diversity in the types of input astrocytes receive, such as the pattern of neuronal input and the type of neurotransmitter. The resultant change in cytosolic calcium after transmitter binding is also diverse, as it depends on the various forms of intracellular signaling cascades and integration of signals.
Acknowledgments
Work supported by NIH-NINDS (Grants #: R01NS097312, R01NS100831, R01NS108686) and Human Frontier Science Program (Research Grant RGP0036/2014) to A.A.
References (71)
- et al.
Gliotransmitters travel in time and space
Neuron
(2014) - et al.
The structural and functional evidence for vesicular release from astrocytes in situ
Brain Res Bull
(2018) - et al.
Intercellular signaling in glial cells: calcium waves and oscillations in response to mechanical stimulation and glutamate
Neuron
(1991) - et al.
Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry
Neuron
(1995) - et al.
Neuronal activity triggers calcium waves in hippocampal astrocyte networks
Neuron
(1992) - et al.
Astrocytes: orchestrating synaptic plasticity?
Neuroscience
(2016) - et al.
Kappa-opioid receptors on astrocytes stimulate L-type Ca2+ channels
Neuroscience
(1993) - et al.
Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors
Neuron
(2004) - et al.
Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD
Cell
(2012) - et al.
Asymmetry of glia near central synapses favors presynaptically directed glutamate escape
Biophys J
(2002)
Endocannabinoids mediate neuron-astrocyte communication
Neuron
Endocannabinoids potentiate synaptic transmission through stimulation of astrocytes
Neuron
Astrocytes are endogenous regulators of basal transmission at central synapses
Cell
Glial calcium signaling and neuron-glia communication
Cell Calcium
Diversity of astroglial functions alludes to subcellular specialisation
Trends Neurosci
TNFalpha controls glutamatergic gliotransmission in the hippocampal dentate gyrus
Neuron
Antidepressants act on glial cells: SSRIs and serotonin elicit astrocyte calcium signaling in the mouse prefrontal cortex
J Psychiatr Res
Probing the complexities of astrocyte calcium signaling
Trends Cell Biol
Functional astrocyte heterogeneity and implications for their role in shaping neurotransmission
Front Cell Neurosci
Astrocytic activation generates de novo neuronal potentiation and memory enhancement
Cell
Modulation of the autonomic nervous system and behaviour by acute glial cell Gq protein-coupled receptor activation in vivo
J Physiol
Astrocytes play a critical role in transient heterosynaptic depression in the rat hippocampal CA1 region
J Physiol
Glutamate released from glial cells synchronizes neuronal activity in the hippocampus
J Neurosci
SNARE protein-dependent glutamate release from astrocytes
J Neurosci
Glutamate-dependent astrocyte modulation of synaptic transmission between cultured hippocampal neurons
Eur J Neurosci
Astrocyte calcium signaling: the third wave
Nat Neurosci
Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate
Nat Neurosci
ATP excites interneurons and astrocytes to increase synaptic inhibition in neuronal networks
J Neurosci
Nucleus basalis-enabled stimulus-specific plasticity in the visual cortex is mediated by astrocytes
Proc Natl Acad Sci USA
Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling
Science
Neuronal activity determines distinct gliotransmitter release from a single astrocyte
eLife
Local Ca2+ detection and modulation of synaptic release by astrocytes
Nat Neurosci
Multiple lines of evidence indicate that gliotransmission does not occur under physiological conditions
J Neurosci
Neuron-astrocyte signaling is preserved in the aging brain
Glia
Endocannabinoids induce lateral long-term potentiation of transmitter release by stimulation of gliotransmission
Cereb Cortex
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