Sustained Neuronal Activity Generated by Glial Plasticity

Astrocytes release gliotransmitters, notably glutamate, that can affect neuronal and synaptic activity. In particular, astrocytic glutamate release results in the generation of NMDA receptor (NMDA-R)-mediated slow inward currents (SICs) in neurons. However, factors underlying the emergence of SICs and their physiological roles are essentially unknown. Here we show that, in acute slices of rat somatosensory thalamus, stimulation of lemniscal or cortical afferents results in a sustained increase of SICs in thalamocortical (TC) neurons that outlasts the duration of the stimulus by 1 h. This long-term enhancement of astrocytic glutamate release is induced by group I metabotropic glutamate receptors and is dependent on astrocytic intracellular calcium. Neuronal SICs are mediated by extrasynaptic NR2B subunit-containing NMDA-Rs and are capable of eliciting bursts. These are distinct from T-type Ca2+ channel-dependent bursts of action potentials and are synchronized in neighboring TC neurons. These findings describe a previously unrecognized form of excitatory, nonsynaptic plasticity in the CNS that feeds forward to generate local neuronal firing long after stimulus termination.

[1]  E. G. Jones,et al.  Switching of NMDA Receptor 2A and 2B Subunits at Thalamic and Cortical Synapses during Early Postnatal Development , 2004, The Journal of Neuroscience.

[2]  T. Takano,et al.  Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo , 2006, Nature Neuroscience.

[3]  Mark Farrant,et al.  NMDA receptor subunits: diversity, development and disease , 2001, Current Opinion in Neurobiology.

[4]  Todd A Fiacco,et al.  Intracellular Astrocyte Calcium Waves In Situ Increase the Frequency of Spontaneous AMPA Receptor Currents in CA1 Pyramidal Neurons , 2004, The Journal of Neuroscience.

[5]  Todd A Fiacco,et al.  Loss of IP3 Receptor-Dependent Ca2+ Increases in Hippocampal Astrocytes Does Not Affect Baseline CA1 Pyramidal Neuron Synaptic Activity , 2008, The Journal of Neuroscience.

[6]  S. Sherman.  Tonic and burst firing: dual modes of thalamocortical relay , 2001, Trends in Neurosciences.

[7]  C. Rose,et al.  Developmental profile and properties of sulforhodamine 101—Labeled glial cells in acute brain slices of rat hippocampus , 2008, Journal of Neuroscience Methods.

[8]  Dany Arsenault,et al.  Developmental remodelling of the lemniscal synapse in the ventral basal thalamus of the mouse , 2006, The Journal of physiology.

[9]  Cathryn L. Kubera,et al.  Astrocytic Purinergic Signaling Coordinates Synaptic Networks , 2005, Science.

[10]  A. Araque,et al.  Endocannabinoids Potentiate Synaptic Transmission through Stimulation of Astrocytes , 2010, Neuron.

[11]  Todd A Fiacco,et al.  Selective Stimulation of Astrocyte Calcium In Situ Does Not Affect Neuronal Excitatory Synaptic Activity , 2007, Neuron.

[12]  T. Takano,et al.  An astrocytic basis of epilepsy , 2005, Nature Medicine.

[13]  H. Bading,et al.  Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways , 2002, Nature Neuroscience.

[14]  Khaleel Bhaukaurally,et al.  Glutamate exocytosis from astrocytes controls synaptic strength , 2007, Nature Neuroscience.

[15]  S. Redman.  Quantal analysis of synaptic potentials in neurons of the central nervous system. , 1990, Physiological reviews.

[16]  H. Parri,et al.  Astrocytes, spontaneity, and the developing thalamus , 2002, Journal of Physiology - Paris.

[17]  R. Guillery,et al.  On the actions that one nerve cell can have on another: distinguishing "drivers" from "modulators". , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Vincenzo Crunelli,et al.  Pacemaker calcium oscillations in thalamic astrocytes in situ , 2001, Neuroreport.

[19]  K. McCarthy,et al.  Hippocampal Astrocytes In Situ Respond to Glutamate Released from Synaptic Terminals , 1996, The Journal of Neuroscience.

[20]  M. de Curtis,et al.  An Excitatory Loop with Astrocytes Contributes to Drive Neurons to Seizure Threshold , 2010, PLoS biology.

[21]  S. Oliet,et al.  Control of Glutamate Clearance and Synaptic Efficacy by Glial Coverage of Neurons , 2001, Science.

[22]  S. Oliet,et al.  Long term potentiation depends on release of D-serine from astrocytes , 2009, Nature.

[23]  Vincenzo Crunelli,et al.  Novel modes of rhythmic burst firing at cognitively-relevant frequencies in thalamocortical neurons , 2008, Brain Research.

[24]  M. Steriade.  Grouping of brain rhythms in corticothalamic systems , 2006, Neuroscience.

[25]  H. Parri,et al.  Sensory and cortical activation of distinct glial cell subtypes in the somatosensory thalamus of young rats , 2010, The European journal of neuroscience.

[26]  A. Araque,et al.  SNARE Protein-Dependent Glutamate Release from Astrocytes , 2000, The Journal of Neuroscience.

[27]  D. Laurie,et al.  Expression and Signaling of Group I Metabotropic Glutamate Receptors in Astrocytes and Microglia , 1999, Journal of neurochemistry.

[28]  Neuronal Synchrony Mediated by Astrocytic Glutamate through Activation of Extrasynaptic NMDA Receptors , 2005, Neuron.

[29]  Eduardo D. Martín,et al.  Synaptically Released Acetylcholine Evokes Ca2+Elevations in Astrocytes in Hippocampal Slices , 2002, The Journal of Neuroscience.

[30]  H. Parri,et al.  Spontaneous astrocytic Ca2+ oscillations in situ drive NMDAR-mediated neuronal excitation , 2001, Nature Neuroscience.

[31]  S. Finkbeiner,et al.  Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. , 1990, Science.

[32]  R. Llinás,et al.  Electrophysiological properties of guinea‐pig thalamic neurones: an in vitro study. , 1984, The Journal of physiology.

[33]  P. Golshani,et al.  Progression of change in NMDA, non-NMDA, and metabotropic glutamate receptor function at the developing corticothalamic synapse. , 1998, Journal of neurophysiology.

[34]  Tullio Pozzan,et al.  Purinergic Receptors Mediate Two Distinct Glutamate Release Pathways in Hippocampal Astrocytes* , 2006, Journal of Biological Chemistry.

[35]  G. Perea,et al.  Astrocytes Potentiate Transmitter Release at Single Hippocampal Synapses , 2007, Science.

[36]  S. Hrabetova,et al.  Distinct NMDA Receptor Subpopulations Contribute to Long-Term Potentiation and Long- Term Depression Induction , 2000, The Journal of Neuroscience.

[37]  J. Meldolesi,et al.  Astrocytes, from brain glue to communication elements: the revolution continues , 2005, Nature Reviews Neuroscience.

[38]  Hee-Sup Shin,et al.  Channel-Mediated Tonic GABA Release from Glia , 2010, Science.

[39]  David F. Meaney,et al.  mGluR5 stimulates gliotransmission in the nucleus accumbens , 2007, Proceedings of the National Academy of Sciences.

[40]  R. North,et al.  NMDA Receptors Mediate Neuron-to-Glia Signaling in Mouse Cortical Astrocytes , 2006, The Journal of Neuroscience.

[41]  J. Lacaille,et al.  GABAergic Network Activation of Glial Cells Underlies Hippocampal Heterosynaptic Depression , 2006, The Journal of Neuroscience.

[42]  M. Deschenes,et al.  The Relay of High-Frequency Sensory Signals in the Whisker-to-Barreloid Pathway , 2003, The Journal of Neuroscience.

[43]  Vincenzo Crunelli,et al.  ATP-Dependent Infra-Slow (<0.1 Hz) Oscillations in Thalamic Networks , 2009, PloS one.

[44]  Harald Sontheimer,et al.  Anion channels in astrocytes: Biophysics, pharmacology, and function , 2006, Glia.

[45]  S. Gobbo,et al.  Astrocytic Glutamate Is Not Necessary for the Generation of Epileptiform Neuronal Activity in Hippocampal Slices , 2006, The Journal of Neuroscience.

[46]  Giorgio Carmignoto,et al.  Glutamate‐mediated astrocyte‐to‐neuron signalling in the rat dorsal horn , 2010, The Journal of physiology.

[47]  M. A. Matthews,et al.  Neuronal maturation and synaptogenesis in the rat ventrobasal complex: Alignment with developmental changes in rate and severity of axon reaction , 1977, The Journal of comparative neurology.

[48]  T. Pozzan,et al.  Intracellular Calcium Oscillations in Astrocytes: A Highly Plastic, Bidirectional Form of Communication between Neurons and Astrocytes In Situ , 1997, The Journal of Neuroscience.

[49]  S. Oliet,et al.  Glia-Derived d-Serine Controls NMDA Receptor Activity and Synaptic Memory , 2006, Cell.

[50]  M. Poo,et al.  Contribution of astrocytes to hippocampal long-term potentiation through release of d-serine , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[51]  J. Isaac,et al.  Developmental synaptic plasticity at the thalamocortical input to barrel cortex: Mechanisms and roles , 2007, Molecular and Cellular Neuroscience.

[52]  R. Nicoll,et al.  NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms , 1993, Trends in Neurosciences.

[53]  Maiken Nedergaard,et al.  Astrocyte activation of presynaptic metabotropic glutamate receptors modulates hippocampal inhibitory synaptic transmission. , 2004, Neuron glia biology.

[54]  M. C. Angulo,et al.  Glutamate Released from Glial Cells Synchronizes Neuronal Activity in the Hippocampus , 2004, The Journal of Neuroscience.

[55]  G. Perea,et al.  Properties of Synaptically Evoked Astrocyte Calcium Signal Reveal Synaptic Information Processing by Astrocytes , 2005, The Journal of Neuroscience.

[56]  Michael J. Jutras,et al.  Synchronous neural activity and memory formation , 2010, Current Opinion in Neurobiology.

[57]  V. Gundersen,et al.  Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate , 2004, Nature Neuroscience.

[58]  H. Killackey,et al.  Ontogenetic changes in the projections of neocortical neurons , 1982, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[59]  C. J. Lee,et al.  Astrocytic control of synaptic NMDA receptors , 2007, The Journal of physiology.

[60]  S. Hughes,et al.  The slow (<1 Hz) rhythm of non-REM sleep: a dialogue between three cardinal oscillators , 2010, Nature Neuroscience.

[61]  D. Attwell,et al.  Do astrocytes really exocytose neurotransmitters? , 2010, Nature Reviews Neuroscience.

[62]  A. Araque,et al.  Tripartite synapses: glia, the unacknowledged partner , 1999, Trends in Neurosciences.

[63]  Vincenzo Crunelli,et al.  Cellular Mechanisms of the Slow (<1 Hz) Oscillation in Thalamocortical Neurons In Vitro , 2002, Neuron.

[64]  B. Connors,et al.  Long-Term Modulation of Electrical Synapses in the Mammalian Thalamus , 2005, Science.

[65]  Todd A Fiacco,et al.  Supporting Online Material Materials and Methods Som Text Figs. S1 to S4 Hippocampal Short-and Long-term Plasticity Are Not Modulated by Astrocyte Ca 2+ Signaling , 2022 .

[66]  S. Goldman,et al.  Astrocyte-mediated potentiation of inhibitory synaptic transmission , 1998, Nature Neuroscience.

[67]  H. Parri,et al.  The role of Ca2+ in the generation of spontaneous astrocytic Ca2+ oscillations , 2003, Neuroscience.

[68]  H. Berg,et al.  Supporting Online Material Materials and Methods Som Text Figs. S1 to S7 Tables S1 to S3 References Movies S1 to S6 Tuned Responses of Astrocytes and Their Influence on Hemodynamic Signals in the Visual Cortex , 2022 .