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Journal ArticleDOI

Local Ca2+ detection and modulation of synaptic release by astrocytes

01 Oct 2011-Nature Neuroscience (Nature Research)-Vol. 14, Iss: 10, pp 1276-1284
TL;DR: Evidence is provided that astrocytes are integrated in local synaptic functioning in adult brain through GTP- and inositol-1,4,5-trisphosphate–dependent signaling and is relevant for basal synaptic function.
Abstract: Astrocytes communicate with synapses by means of intracellular calcium ([Ca(2+)](i)) elevations, but local calcium dynamics in astrocytic processes have never been thoroughly investigated. By taking advantage of high-resolution two-photon microscopy, we identify the characteristics of local astrocyte calcium activity in the adult mouse hippocampus. Astrocytic processes showed intense activity, triggered by physiological transmission at neighboring synapses. They encoded synchronous synaptic events generated by sparse action potentials into robust regional (∼12 μm) [Ca(2+)](i) elevations. Unexpectedly, they also sensed spontaneous synaptic events, producing highly confined (∼4 μm), fast (millisecond-scale) miniature Ca(2+) responses. This Ca(2+) activity in astrocytic processes is generated through GTP- and inositol-1,4,5-trisphosphate-dependent signaling and is relevant for basal synaptic function. Thus, buffering astrocyte [Ca(2+)](i) or blocking a receptor mediating local astrocyte Ca(2+) signals decreased synaptic transmission reliability in minimal stimulation experiments. These data provide direct evidence that astrocytes are integrated in local synaptic functioning in adult brain.
Citations
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Journal ArticleDOI
19 Feb 2014-Neuron
TL;DR: It is proposed that astrocytes mainly signal through high-affinity slowly desensitizing receptors to modulate neurons and perform integration in spatiotemporal domains complementary to those of neurons.

990 citations


Cites background from "Local Ca2+ detection and modulation..."

  • ...Recent studies revealed, however, that small, rapid, and localized Ca2+ responses can be elicited in microdomains of astrocytic processes by minimal synaptic activity (Di Castro et al., 2011; Panatier et al., 2011)....

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  • ...…astrocytic Ca2+ activation, initially restricted to a microdomain, expands beyond the local subcompartment into another process (Figure 2B) and eventually the whole cell (Figure 2C) (Castonguay et al., 2001; Di Castro et al., 2011; Panatier et al., 2011; Pasti et al., 1997; Zonta et al., 2003)....

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  • ...Also, Di Castro et al. (2011) reported complex spatial-temporal properties of Ca2+ responses elicited by axonal firing in astrocytic processes, sometimes with multiple initiation points....

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  • ...…space integration encompasses faster and more local changes based on the rapid activation of small compartments along the astrocytic processes (Di Castro et al., 2011; Grosche et al., 1999; Panatier et al., 2011; Pasti et al., 1997) up to complex multiastrocytic and neuronal interactions that…...

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  • ...…which mimic the typical oscillatory behavior of astrocyte Ca2+ signals both at rest (Nett et al., 2002) and in response to neuronal activity (Di Castro et al., 2011; Pasti et al., 1997), resulted in multiple glutamate release episodes and, in turn, repetitive activation of neuronal receptors....

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Journal ArticleDOI
TL;DR: Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.
Abstract: Astrocytes are neural cells of ectodermal, neuroepithelial origin that provide for homeostasis and defense of the central nervous system (CNS). Astrocytes are highly heterogeneous in morphological appearance; they express a multitude of receptors, channels, and membrane transporters. This complement underlies their remarkable adaptive plasticity that defines the functional maintenance of the CNS in development and aging. Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.

921 citations


Cites background from "Local Ca2+ detection and modulation..."

  • ...Compartmentalization of Ca(2) signaling in fine astroglial processes may involve specific positioning of mitochondria which tend to immobilize themselves in sites of focal [Ca(2) ]i spikes (423)....

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  • ...Usually [Ca(2) ]i transients were larger and longer in the soma; in the processes both frequent and relatively fast [Ca(2) ]i fluctuations (423, 1308, 1831) as well as very slow (~40 s) events, defined as “Ca(2) twinkles” (821) were reported....

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  • ...Both types of localized Ca(2) dynamics in astroglial processes were associated with InsP3R-mediated Ca 2 release; they were inhibited by intracellular injection of heparin and were almost completely eliminated in InsP3R2 / mice (423)....

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  • ...In the distal processes, Ca(2) signals occur as localized microdomains either spontaneously without obvious link to neuronal activity (821, 1208, 1609) or in response to synaptic stimulation (423, 609, 821, 1225, 1660)....

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  • ...Importantly, Ca(2) mobilizing mechanisms differ between astrocytes from different brain regions: Ca(2) microdomains in Bergmann glia and in the main processes of hippocampal astrocytes were mediated solely by InsP3 receptors (423, 879)....

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Journal ArticleDOI
TL;DR: New insights herald the concept that astrocytes represent a diverse population of genetically tractable cells that mediate neural circuit–specific roles in health and disease.
Abstract: Astrocytes tile the entire CNS. They are vital for neural circuit function, but have traditionally been viewed as simple, homogenous cells that serve the same essential supportive roles everywhere. Here, we summarize breakthroughs that instead indicate that astrocytes represent a population of complex and functionally diverse cells. Physiological diversity of astrocytes is apparent between different brain circuits and microcircuits, and individual astrocytes display diverse signaling in subcellular compartments. With respect to injury and disease, astrocytes undergo diverse phenotypic changes that may be protective or causative with regard to pathology in a context-dependent manner. These new insights herald the concept that astrocytes represent a diverse population of genetically tractable cells that mediate neural circuit-specific roles in health and disease.

821 citations

Journal ArticleDOI
TL;DR: The discovery that transient elevations of calcium concentration occur in astrocytes, and release 'gliotransmitters' which act on neurons and vascular smooth muscle, led to the idea that astroCytes are powerful regulators of neuronal spiking, synaptic plasticity and brain blood flow.
Abstract: The discovery that transient elevations of calcium concentration occur in astrocytes, and release 'gliotransmitters' which act on neurons and vascular smooth muscle, led to the idea that astrocytes are powerful regulators of neuronal spiking, synaptic plasticity and brain blood flow. These findings were challenged by a second wave of reports that astrocyte calcium transients did not mediate functions attributed to gliotransmitters and were too slow to generate blood flow increases. Remarkably, the tide has now turned again: the most important calcium transients occur in fine astrocyte processes not resolved in earlier studies, and new mechanisms have been discovered by which astrocyte [Ca(2+)]i is raised and exerts its effects. Here we review how this third wave of discoveries has changed our understanding of astrocyte calcium signaling and its consequences for neuronal function.

673 citations

01 Jan 2007
TL;DR: Results indicate that astrocytes are actively involved in the transfer and storage of synaptic information and mGluR-mediated but N-methyl-d-aspartate receptor–independent plasticity is observed.
Abstract: Astrocytes play active roles in brain physiology. They respond to neurotransmitters and modulate neuronal excitability and synaptic function. However, the influence of astrocytes on synaptic transmission and plasticity at the single synapse level is unknown. Ca2+ elevation in astrocytes transiently increased the probability of transmitter release at hippocampal area CA3-CA1 synapses, without affecting the amplitude of synaptic events. This form of short-term plasticity was due to the release of glutamate from astrocytes, a process that depended on Ca2+ and soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) protein and that activated metabotropic glutamate receptors (mGluRs). The transient potentiation of transmitter release became persistent when the astrocytic signal was temporally coincident with postsynaptic depolarization. This persistent plasticity was mGluR-mediated but N-methyl-d-aspartate receptor–independent. These results indicate that astrocytes are actively involved in the transfer and storage of synaptic information.

537 citations

References
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Journal ArticleDOI
TL;DR: There is an emerging view, which is reviewed herein, in which brain function actually arises from the coordinated activity of a network comprising both neurons and glia, rather than the classically accepted paradigm that brain function results exclusively from neuronal activity.

1,481 citations

Journal ArticleDOI
26 Jan 2001-Science
TL;DR: It is shown that few synapses form in the absence of glial cells and that the fewsynapses that do form are functionally immature, and that CNS synapse number can be profoundly regulated by nonneuronal signals.
Abstract: Although astrocytes constitute nearly half of the cells in our brain, their function is a long-standing neurobiological mystery. Here we show by quantal analyses, FM1-43 imaging, immunostaining, and electron microscopy that few synapses form in the absence of glial cells and that the few synapses that do form are functionally immature. Astrocytes increase the number of mature, functional synapses on central nervous system (CNS) neurons by sevenfold and are required for synaptic maintenance in vitro. We also show that most synapses are generated concurrently with the development of glia in vivo. These data demonstrate a previously unknown function for glia in inducing and stabilizing CNS synapses, show that CNS synapse number can be profoundly regulated by nonneuronal signals, and raise the possibility that glia may actively participate in synaptic plasticity.

1,302 citations


"Local Ca2+ detection and modulation..." refers background in this paper

  • ...Studies in cell cultures suggest that astrocytes contribute to this functio...

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Journal ArticleDOI
14 Jan 2010-Nature
TL;DR: It is demonstrated that Ca2+-dependent release of d-serine from an astrocyte controls NMDAR-dependent plasticity in many thousands of excitatory synapses nearby.
Abstract: Long-term potentiation (LTP) of synaptic transmission provides an experimental model for studying mechanisms of memory. The classical form of LTP relies on N-methyl-D-aspartate receptors (NMDARs), and it has been shown that astroglia can regulate their activation through Ca(2+)-dependent release of the NMDAR co-agonist D-serine. Release of D-serine from glia enables LTP in cultures and explains a correlation between glial coverage of synapses and LTP in the supraoptic nucleus. However, increases in Ca(2+) concentration in astroglia can also release other signalling molecules, most prominently glutamate, ATP and tumour necrosis factor-alpha, whereas neurons themselves can synthesize and supply D-serine. Furthermore, loading an astrocyte with exogenous Ca(2+) buffers does not suppress LTP in hippocampal area CA1 (refs 14-16), and the physiological relevance of experiments in cultures or strong exogenous stimuli applied to astrocytes has been questioned. The involvement of glia in LTP induction therefore remains controversial. Here we show that clamping internal Ca(2+) in individual CA1 astrocytes blocks LTP induction at nearby excitatory synapses by decreasing the occupancy of the NMDAR co-agonist sites. This LTP blockade can be reversed by exogenous D-serine or glycine, whereas depletion of D-serine or disruption of exocytosis in an individual astrocyte blocks local LTP. We therefore demonstrate that Ca(2+)-dependent release of D-serine from an astrocyte controls NMDAR-dependent plasticity in many thousands of excitatory synapses nearby.

1,180 citations

Journal ArticleDOI
01 Jun 1996-Neuron
TL;DR: It is found that hypertonic solutions do not act through changes in intracellular calcium, which means that the synaptic release probability depends on the size of the readily releasable pool.

1,034 citations

Journal ArticleDOI
02 Sep 2004-Neuron
TL;DR: The results reveal a distinct mechanism for neuronal excitation and synchrony and highlight a functional link between astrocytic glutamate and extrasynaptic NMDA receptors.

847 citations