Computational modeling of paroxysmal depolarization shifts in neurons induced by the glutamate release from astrocytes

Recent experimental studies have shown that astrocytes respond to external stimuli with a transient increase of the intracellular calcium concentration or can exhibit self-sustained spontaneous activity. Both evoked and spontaneous astrocytic calcium oscillations are accompanied by exocytosis of glutamate caged in astrocytes leading to paroxysmal depolarization shifts (PDS) in neighboring neurons. Here, we present a simple mathematical model of the interaction between astrocytes and neurons that is able to numerically reproduce the experimental results concerning the initiation of the PDS. The timing of glutamate release from the astrocyte is studied by means of a combined modeling of a vesicle cycle and the dynamics of SNARE-proteins. The neuronal slow inward currents (SICs), induced by the astrocytic glutamate and leading to PDS, are modeled via the activation of presynaptic glutamate receptors. The dependence of the bidirectional communication between neurons and astrocytes on the concentration of glutamate transporters is analyzed, as well. Our numerical results are in line with experimental findings showing that astrocyte can induce synchronous PDSs in neighboring neurons, resulting in a transient synchronous spiking activity.

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

[2]  A Goldbeter,et al.  Bursting, chaos and birhythmicity originating from self-modulation of the inositol 1,4,5-trisphosphate signal in a model for intracellular Ca2+ oscillations , 1999, Bulletin of mathematical biology.

[3]  R. Orkand,et al.  Modification of potassium movement through the retina of the drone (Apis mellifera male) by glial uptake. , 1983, The Journal of physiology.

[4]  Mitsunori Fukuda,et al.  Synaptotagmin IV regulates glial glutamate release. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

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

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

[7]  Zhuan Zhou,et al.  “Kiss-and-Run” Glutamate Secretion in Cultured and Freshly Isolated Rat Hippocampal Astrocytes , 2005, The Journal of Neuroscience.

[8]  C. Jahr,et al.  Glial Contribution to Glutamate Uptake at Schaffer Collateral–Commissural Synapses in the Hippocampus , 1998, The Journal of Neuroscience.

[9]  Eshel Ben-Jacob,et al.  The Astrocyte as a Gatekeeper of Synaptic Information Transfer , 2006, Neural Computation.

[10]  A Goldbeter,et al.  Minimal model for signal-induced Ca2+ oscillations and for their frequency encoding through protein phosphorylation. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

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

[12]  D. Rusakov.  The role of perisynaptic glial sheaths in glutamate spillover and extracellular Ca(2+) depletion. , 2001, Biophysical journal.

[13]  A. Araque,et al.  Glutamate‐dependent astrocyte modulation of synaptic transmission between cultured hippocampal neurons , 1998, The European journal of neuroscience.

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

[15]  T. Südhof,et al.  The Synaptic Vesicle Cycle in the Nerve Terminal , 1999 .

[16]  A. Charles,et al.  Intercellular calcium waves in glia , 1998, Glia.

[17]  P. Haydon,et al.  Physiological astrocytic calcium levels stimulate glutamate release to modulate adjacent neurons. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[18]  K. Zahs,et al.  Calcium Waves in Retinal Glial Cells , 1997, Science.

[19]  Torsten Olsson,et al.  α1-Adrenergic Modulation of Metabotropic Glutamate Receptor-induced Calcium Oscillations and Glutamate Release in Astrocytes* , 2001, The Journal of Biological Chemistry.

[20]  S. Nadkarni,et al.  Modeling synaptic transmission of the tripartite synapse , 2007, Physical biology.

[21]  Michael M. Halassa,et al.  Synaptic Islands Defined by the Territory of a Single Astrocyte , 2007, The Journal of Neuroscience.

[22]  Eduardo Soriano,et al.  Neuronal Activity Regulates Correlated Network Properties of Spontaneous Calcium Transients in Astrocytes In Situ , 2002, The Journal of Neuroscience.

[23]  Mark K. Bennett,et al.  A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion , 1993, Cell.

[24]  W. Holmes.  Modeling the effect of glutamate diffusion and uptake on NMDA and non-NMDA receptor saturation. , 1995, Biophysical journal.

[25]  G. Bi,et al.  Synaptic Modifications in Cultured Hippocampal Neurons: Dependence on Spike Timing, Synaptic Strength, and Postsynaptic Cell Type , 1998, The Journal of Neuroscience.

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

[27]  Maja Potokar,et al.  Properties of Ca2+‐dependent exocytosis in cultured astrocytes , 2004, Glia.

[28]  Maiken Nedergaard,et al.  Astrocytic glutamate release-induced transient depolarization and epileptiform discharges in hippocampal CA1 pyramidal neurons. , 2005, Journal of neurophysiology.

[29]  Fang Liu,et al.  Glutamate-mediated astrocyte–neuron signalling , 1994, Nature.

[30]  H. Markram,et al.  Dendritic calcium transients evoked by single back‐propagating action potentials in rat neocortical pyramidal neurons. , 1995, The Journal of physiology.

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

[32]  D. Kullmann,et al.  Hippocampal synapses: do they talk to their neighbours? , 1999, Trends in Neurosciences.

[33]  Dmitry E. Postnov,et al.  Functional modeling of neural-glial interaction , 2007, Biosyst..

[34]  Suhita Nadkarni,et al.  Synaptic inhibition and pathologic hyperexcitability through enhanced neuron-astrocyte interaction: a modeling study. , 2005, Journal of integrative neuroscience.

[35]  D. Kullmann,et al.  Extrasynaptic Glutamate Diffusion in the Hippocampus: Ultrastructural Constraints, Uptake, and Receptor Activation , 1998, The Journal of Neuroscience.

[36]  Suhita Nadkarni,et al.  Dressed neurons: modeling neural–glial interactions , 2004, Physical biology.

[37]  W. Senn,et al.  Transmitter concentration profiles in the synaptic cleft: an analytical model of release and diffusion. , 1996, Biophysical journal.

[38]  H. V. Gersdorff,et al.  Dynamics of synaptic vesicle fusion and membrane retrieval in synaptic terminals , 1994, Nature.

[39]  Ralf Schneggenburger,et al.  Intracellular calcium dependence of transmitter release rates at a fast central synapse , 2000, Nature.

[40]  S. Oloff,et al.  Hippocampal astrocytes in situ exhibit calcium oscillations that occur independent of neuronal activity. , 2002, Journal of neurophysiology.

[41]  N. Danbolt.  Glutamate uptake , 2001, Progress in Neurobiology.

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

[43]  T. Südhof.  The synaptic vesicle cycle , 2004 .

[44]  A. Destexhe.  Kinetic Models of Synaptic Transmission , 1997 .

[45]  V. Parpura,et al.  Vesicular Glutamate Transporter-Dependent Glutamate Release from Astrocytes , 2004, The Journal of Neuroscience.

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

[47]  Dwight E Bergles,et al.  Clearance of glutamate inside the synapse and beyond , 1999, Current Opinion in Neurobiology.

[48]  T. Fellin,et al.  Do astrocytes contribute to excitation underlying seizures? , 2005, Trends in molecular medicine.

[49]  A Goldbeter,et al.  Complex intracellular calcium oscillations. A theoretical exploration of possible mechanisms. , 1997, Biophysical chemistry.

[50]  E. Neher.  Vesicle Pools and Ca2+ Microdomains: New Tools for Understanding Their Roles in Neurotransmitter Release , 1998, Neuron.

[51]  E. Neher,et al.  Emerging Roles of Presynaptic Proteins in Ca++-Triggered Exocytosis , 2002, Science.

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

[53]  H. Jingami,et al.  Negative Cooperativity of Glutamate Binding in the Dimeric Metabotropic Glutamate Receptor Subtype 1* , 2004, Journal of Biological Chemistry.

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

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

[56]  J. Keizer,et al.  Two roles of Ca2+ in agonist stimulated Ca2+ oscillations. , 1992, Biophysical journal.

[57]  Amin Derouiche,et al.  Astrocytic exocytosis vesicles and glutamate: A high‐resolution immunofluorescence study , 2005, Glia.

[58]  Michela Matteoli,et al.  Synaptobrevin2‐expressing vesicles in rat astrocytes: insights into molecular characterization, dynamics and exocytosis , 2006, The Journal of physiology.

[59]  P. Haydon.  Glia: listening and talking to the synapse , 2001, Nature Reviews Neuroscience.

[60]  Boris Barbour,et al.  Nonvesicular release of neurotransmitter , 1993, Neuron.

[61]  W. Kloot,et al.  At the frog neuromuscular junction prostaglandin synthase inhibitors depress and PGE2 partially restores quantal acetylcholine release , 1982, Brain Research.

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

[63]  Gary Matthews,et al.  Calcium dependence of the rate of exocytosis in a synaptic terminal , 1994, Nature.

[64]  D. Johnston,et al.  Regulation of Synaptic Efficacy by Coincidence of Postsynaptic APs and EPSPs , 1997 .

[65]  Michela Matteoli,et al.  Vesicular transmitter release from astrocytes , 2006, Glia.

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

[67]  Leif Hertz,et al.  Kinetic characteristics of the glutamate uptake into normal astrocytes in cultures , 1978, Neurochemical Research.

[68]  R. Robitaille,et al.  Modulation of Synaptic Efficacy and Synaptic Depression by Glial Cells at the Frog Neuromuscular Junction , 1998, Neuron.

[69]  X J Wang,et al.  Calcium coding and adaptive temporal computation in cortical pyramidal neurons. , 1998, Journal of neurophysiology.

[70]  L. Stryer,et al.  Molecular model for receptor-stimulated calcium spiking. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[71]  John Rinzel,et al.  Intrinsic and network rhythmogenesis in a reduced traub model for CA3 neurons , 1995, Journal of Computational Neuroscience.

[72]  D. Rusakov,et al.  Asymmetry of glia near central synapses favors presynaptically directed glutamate escape. , 2002, Biophysical journal.