Fellin T, Pascual O, Gobbo S, Pozzan T, Haydon PG, Carmignoto G. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43: 729-743

Istituto CNR di Neuroscienze, Università di Padova, viale G. Colombo 3, 35121, Italy.
Neuron (Impact Factor: 15.05). 10/2004; 43(5):729-43. DOI: 10.1016/j.neuron.2004.08.011
Source: PubMed


Fast excitatory neurotransmission is mediated by activation of synaptic ionotropic glutamate receptors. In hippocampal slices, we report that stimulation of Schaffer collaterals evokes in CA1 neurons delayed inward currents with slow kinetics, in addition to fast excitatory postsynaptic currents. Similar slow events also occur spontaneously, can still be observed when neuronal activity and synaptic glutamate release are blocked, and are found to be mediated by glutamate released from astrocytes acting preferentially on extrasynaptic NMDA receptors. The slow currents can be triggered by stimuli that evoke Ca2+ oscillations in astrocytes, including photolysis of caged Ca2+ in single astrocytes. As revealed by paired recording and Ca2+ imaging, a striking feature of this NMDA receptor response is that it occurs synchronously in multiple CA1 neurons. Our results reveal a distinct mechanism for neuronal excitation and synchrony and highlight a functional link between astrocytic glutamate and extrasynaptic NMDA receptors.

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    • ", e . g . , glutamate or the tissue - type plasminogen activator ( tPA ) from astrocytes ( Liu et al . , 2004 ; Mothet et al . , 2005 ; Casse et al . , 2012 ) . The released glutamate has further effects on neighboring hippocampal neurons by triggering a slow , transient current , which in turn can activate NMDA receptors ( Angulo et al . , 2004 ; Fellin et al . , 2004 ) or by activating GluK5 - containing kainate receptors on adjacent interneurons and thus increases their inhibitory postsynaptic currents ( Rodríguez - Moreno and Lerma , 1998 ; Liu et al . , 2004 ) . Thus , kainate receptors in astrocytes serve as sensors for extracellular glutamate in astrocytes thereby preventing excitotoxicity . Du"
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    ABSTRACT: Glutamate receptors play an important role in the function of astrocytes. Among their tasks is the regulation of gliotransmission, gene expression and exocytosis of the tissue-type plasminogen activator (tPA), which has an enhancing effect on N-methyl-D-aspartate (NMDA) receptors and thus prevent over-excitation of neighboring neurons. The kainate receptor GluK2, which is expressed in neurons and astrocytes, is under tight regulation of the PI3-kinase SGK pathway as shown in neurons. SGK1 targets include N-myc downstream-regulated genes (NDRGs) 1 and 2 (NDRG1, NDRG2), proteins with elusive function. In the present study, we analyzed the effects of SGK1, NDRG1, and NDRG2 on GluK2 current amplitude and plasma membrane localization in astrocytes and heterologous expression. We demonstrate that NDRG1 and NDRG2 themselves have no effect on GluK2 current amplitudes in heterologous expressed ion channels. However, when NDRG2 is coexpressed with GluK2 and SGK1, the stimulating effect of SGK1 on GluK2 is suppressed both in heterologous expression and in astrocytes. Here, we reveal a new negative feedback mechanism, whereby GluK2 stimulation by SGK1 is regulated by parallel phosphorylation of NDRG2. This regulation of GluK2 by SGK1 and NDRG2 in astrocytes may play an important role in gliotransmission, modulation of gene expression and regulation of exocytosis of tPA.
    Frontiers in Cellular Neuroscience 10/2015; 9:387. DOI:10.3389/fncel.2015.00387 · 4.29 Impact Factor
    • "It is now clear that astrocytes respond to the excitatory neurotransmitter glutamate with Ca 21 elevations mediated by metabotropic glutamate receptors (mGluR) and in response to this activation release various gliotransmitters , including glutamate, ATP, and D-serine that can exert multiple actions on neuronal communication, the nature of which depends on the specific type of targeted neuronal receptor and circuit. For example, astrocyte-derived glutamate can potentiate excitatory synaptic transmission through activation of presynaptic mGluR or N-methyl-D-aspartate (NMDA) receptors (Jourdain et al., 2007; Navarrete and Araque , 2010; Navarrete et al., 2012), but it can also favor neuronal synchronies by inducing slow inward currents mediated by postsynaptic NMDA receptors (D'Ascenzo et al., 2007; Fellin et al., 2004; Pirttimaki et al., 2013). Whether astrocytes can similarly respond to other neurotransmitters such as GABA is relatively unexplored and of great importance (for reviews, see Losi et al., 2014; Velez-Fort et al., 2011). "
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    Glia 10/2015; DOI:10.1002/glia.22933 · 6.03 Impact Factor
    • "On the other hand, single-and two-photon un-caging stimulation has been important to demonstrate the Ca2+-dependent release of gliotransmitters by astrocytes in acute brain slices (Fellin et al., 2004; Gordon et al., 2009; Liu et al., 2004; Perea and Araque, 2007) as well as permitting neuronal activation and inhibition in freely moving animals (Aravanis et al., 2007; Gradinaru et al., 2009; Wyart et al., 2009). In conjunction with spatiotemporally resolved photo-stimulation techniques, these photo-sensible tools represent the most promising alternative to electrical stimulation devices to control the activity of specific types of brain cells in time and space with sufficient precision. "
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    ABSTRACT: Present neurobiological concepts regarding superior cognitive functions are based on synaptic neurotransmission and neuronal plasticity. However, the diversity and complexity of neuro-cortical connections, circuits, maps and their relationships with memory, learning and other superior cognitive functions are not fully explained by the present neurobiological paradigms. Recent discoveries concerning the ability of neuronal cells to perceive and process very-weak electromagnetic information suggest a possible role of bio-photons generated as consequence of neuronal and astroglial metabolisms in a wide diversity of cognitive representations. Moreover, the finding that human brain has magnetite nanoparticles opens new possibilities about the role of these nano-crystals in information processing and memory. In the present chapter, a previously advanced model (Neuron-Astroglial Communication in Short-Term Memory: Bio-Electric, Bio-Magnetic and Bio-Photonic Signals?) is developed. Based in the ability of neurons and astrocytes to generate bio-photons as consequence of their metabolic activities, I propose the generation of innumerable bio-phonic-mediated nano-holograms, which are produced and modulated by magnetite nano-crystals associated to neuronal and astroglial membranes in the cerebral neocortex. Specifically, it is suggested that bio-photons generated by neuronal and astroglial cells may produce multichannel holographic pictures through their interaction with single domain and/or superparamagnetic magnetite nanoparticles, explaining retrieval of short-term and long-term memories as well as other neuro- cognitive representations such as the ―images‖ generated in dreams. Bio-chemic, bio- electric, bio-magnetic and bio-photonic activities in the cerebral cortex are not independent bio-physical phenomena, suggesting that interactions among these signals may contribute to information exchange and processing in the neocortex. This hypothesis proposes that the interactions among bio-chemic, bio-electric, bio-magnetic and bio- photonic activities in neurons and astrocytes in the human cerebral neocortex are not epiphenomena of the cerebral activity but they play important roles in cognitive functions, providing new perspectives for better understand complex cognitive functions.
    Horizons in Neuroscience Research. Volume 20, Edited by Andres Costa and Eugenio Villalba, 07/2015: chapter Holographic Memory: Magnetite Nano-Devices for Bio-Photonic Representations in the Human Brain Neocortex: pages 1-40; Nova Science Publishers., ISBN: 978-1-63482-817-8
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