Evidence for Ectopic Neurotransmission at a Neuronal Synapse

Neurotransmitter release is well known to occur at specialized synaptic regions that include presynaptic active zones and postsynaptic densities. At cholinergic synapses in the chick ciliary ganglion, however, membrane formations and physiological measurements suggest that release distant from postsynaptic densities can activate the predominantly extrasynaptic α7 nicotinic receptor subtype. We explored such ectopic neurotransmission with a novel model synapse that combines Monte Carlo simulations with high-resolution serial electron microscopic tomography. Simulated synaptic activity is consistent with experimental recordings of miniature excitatory postsynaptic currents only when ectopic transmission is included in the model, broadening the possibilities for mechanisms of neuronal communication.

[1]  J. Diamond.  Neuronal Glutamate Transporters Limit Activation of NMDA Receptors by Neurotransmitter Spillover on CA1 Pyramidal Cells , 2001, The Journal of Neuroscience.

[2]  Mark Farrant,et al.  Differences in Synaptic GABAA Receptor Number Underlie Variation in GABA Mini Amplitude , 1997, Neuron.

[3]  J. S. Coggan,et al.  Synaptic Currents Generated by Neuronal Acetylcholine Receptors Sensitive to α-Bungarotoxin , 1996, Neuron.

[4]  R. Silver,et al.  The density of AMPA receptors activated by a transmitter quantum at the climbing fibre‐Purkinje cell synapse in immature rats , 2003, The Journal of physiology.

[5]  T. Sixma,et al.  A glia-derived acetylcholine-binding protein that modulates synaptic transmission , 2001, Nature.

[6]  Mark Ellisman,et al.  Synaptically Driven Calcium Transients via Nicotinic Receptors on Somatic Spines , 2001, The Journal of Neuroscience.

[7]  M H Ellisman,et al.  Synaptic Vesicle Populations in Saccular Hair Cells Reconstructed by Electron Tomography , 1999, The Journal of Neuroscience.

[8]  T. Bartol,et al.  Monte Carlo simulation of miniature endplate current generation in the vertebrate neuromuscular junction. , 1991, Biophysical journal.

[9]  T. Sejnowski,et al.  Independent Sources of Quantal Variability at Single Glutamatergic Synapses , 2003, The Journal of Neuroscience.

[10]  D. K. Berg,et al.  Voltage-Gated Channels Block Nicotinic Regulation of CREB Phosphorylation and Gene Expression in Neurons , 2001, Neuron.

[11]  刘金明,et al.  IL-13受体α2降低血吸虫病肉芽肿的炎症反应并延长宿主存活时间[英]/Mentink-Kane MM,Cheever AW，Thompson RW，et al//Proc Natl Acad Sci U S A , 2005 .

[12]  Terrence J Sejnowski,et al.  A Monte Carlo model reveals independent signaling at central glutamatergic synapses. , 2002, Biophysical journal.

[13]  E. Ullian,et al.  Rapid Synaptic Transmission in the Avian Ciliary Ganglion Is Mediated by Two Distinct Classes of Nicotinic Receptors , 1997, The Journal of Neuroscience.

[14]  T. Bartol,et al.  Miniature endplate current rise times less than 100 microseconds from improved dual recordings can be modeled with passive acetylcholine diffusion from a synaptic vesicle. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[15]  T. Sixma,et al.  Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors , 2001, Nature.

[16]  Pb Sargent,et al.  Perisynaptic surface distribution of multiple classes of nicotinic acetylcholine receptors on neurons in the chicken ciliary ganglion , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[17]  P. Sargent,et al.  Synaptic vesicle recycling at two classes of release sites in giant nerve terminals of the embryonic chicken ciliary ganglion , 2002, The Journal of comparative neurology.

[18]  D. Wilkin,et al.  Neuron , 2001, Brain Research.

[19]  C. Jahr,et al.  Ectopic Release of Synaptic Vesicles , 2003, Neuron.

[20]  D. Zenisek,et al.  Transport, capture and exocytosis of single synaptic vesicles at active zones , 2000, Nature.

[21]  M. Shinitzky.  An efficient method for modulation of cholesterol level in cell membranes , 1978, FEBS letters.

[22]  R. Silver,et al.  Spillover of Glutamate onto Synaptic AMPA Receptors Enhances Fast Transmission at a Cerebellar Synapse , 2002, Neuron.

[23]  R. Loring,et al.  Localization of α-bungarotoxin binding sites in the ciliary ganglion of the embryonic chick: An autoradiographic study at the light and electron microscopic level , 1985, Neuroscience.

[24]  Erik De Schutter,et al.  Computational neuroscience : realistic modeling for experimentalists , 2000 .

[25]  Martin Wilson,et al.  Variation in GABA mini amplitude is the consequence of variation in transmitter concentration , 1995, Neuron.

[26]  J. Couraud,et al.  Acetylcholinesterase Molecular Forms in Chick Ciliary Ganglion: Pre‐ and Postsynaptic Distribution Derived from Denervation, Axotomy, and Double Section , 1980, Journal of neurochemistry.

[27]  P. Pugh,et al.  Expression and channel properties of alpha-bungarotoxin-sensitive acetylcholine receptors on chick ciliary and choroid neurons. , 2000, Journal of neurophysiology.

[28]  J. Stiles,et al.  The temperature sensitivity of miniature endplate currents is mostly governed by channel gating: evidence from optimized recordings and Monte Carlo simulations. , 1999, Biophysical journal.

[29]  H Korn,et al.  Intrinsic quantal variability due to stochastic properties of receptor-transmitter interactions. , 1992, Science.

[30]  Mark H. Ellisman,et al.  Serial Section Electron Tomography: A Method for Three-Dimensional Reconstruction of Large Structures , 1994, NeuroImage.

[31]  William E. Lorensen,et al.  Marching cubes: A high resolution 3D surface construction algorithm , 1987, SIGGRAPH.

[32]  D. K. Berg,et al.  Neurons Can Maintain Multiple Classes of Nicotinic Acetylcholine Receptors Distinguished by Different Subunit Compositions (*) , 1995, The Journal of Biological Chemistry.

[33]  Mark H Ellisman,et al.  Ultrastructure of a Somatic Spine Mat for Nicotinic Signaling in Neurons , 2002, The Journal of Neuroscience.

[34]  H Korn,et al.  The effects of geometrical parameters on synaptic transmission: a Monte Carlo simulation study. , 1997, Biophysical journal.

[35]  Joel R. Stiles,et al.  Acetylcholinesterase density and turnover number at frog neuromuscular junctions, with modeling of their role in synaptic function , 1994, Neuron.

[36]  D. K. Berg,et al.  Nicotinic Acetylcholine Receptors Containing α7 Subunits Are Required for Reliable Synaptic Transmission In Situ , 1999, The Journal of Neuroscience.

[37]  Mark H. Ellisman,et al.  Neuronal Acetylcholine Receptors with α7 Subunits Are Concentrated on Somatic Spines for Synaptic Signaling in Embryonic Chick Ciliary Ganglia , 1999, The Journal of Neuroscience.

[38]  J. Massoulie,et al.  Active-site catalytic efficiency of acetylcholinesterase molecular forms in Electrophorus, torpedo, rat and chicken. , 1978, European journal of biochemistry.

[39]  G. Spirou,et al.  Optimizing Synaptic Architecture and Efficiency for High-Frequency Transmission , 2002, Neuron.

[40]  W. Gibson,et al.  Synaptic transmission at visualized sympathetic boutons: stochastic interaction between acetylcholine and its receptors. , 1997, Biophysical journal.