Modulation of cellular and synaptic variability in the lamprey spinal cord.

Variability is increasingly recognized as a characteristic feature of cellular, synaptic, and network properties. While studies have traditionally focused on mean values, significant effects can result from changes in variance. This study has examined cellular and synaptic variability in the lamprey spinal cord and its modulation by the neuropeptide substance P. Cellular and synaptic variability differed in different types of cell and synapse. Substance P reduced the variability of subthreshold locomotor-related depolarizations and spiking in motor neurons during network activity. These effects were associated with a reduction in the variability of spiking in glutamatergic excitatory network interneurons and with a reduction in the variance of excitatory interneuron-evoked excitatory postsynaptic potentials (EPSPs). Substance P also reduced the variance of postsynpatic potentials (PSPs) from crossing inhibitory and excitatory interneurons, but it increased the variance of inhibitory postsynpatic potentials (IPSPs) from ipsilateral inhibitory interneurons. The effects on the variance of different PSPs could occur with or without changes in the PSP amplitude. The reduction in the variance of excitatory interneuron-evoked EPSPs was protein kinase A, calcium, and N-methyl-d-aspartate (NMDA) dependent. The NMDA dependence suggested that substance P was acting postsynaptically. This was supported by the reduced variability of postsynaptic responses to glutamate by substance P. However, ultrastructural analyses suggested that there may also be a presynaptic component to the modulation, because substance P reduced the variability of synaptic vesicle diameters in putative glutamatergic terminals. These results suggest that cellular and synaptic variability can be targeted for modulation, making it an additional source of spinal cord plasticity.

[1]  I. Soltesz,et al.  Febrile seizures in the developing brain result in persistent modification of neuronal excitability in limbic circuits , 1999, Nature Medicine.

[2]  S. Grillner,et al.  Identification of excitatory interneurons contributing to generation of locomotion in lamprey: structure, pharmacology, and function. , 1989, Journal of neurophysiology.

[3]  I. Soltesz,et al.  Modulation of network behaviour by changes in variance in interneuronal properties , 2002, The Journal of physiology.

[4]  I. V. Orekhova,et al.  Cycle-to-cycle variability of neuromuscular activity in Aplysia feeding behavior. , 2004, Journal of neurophysiology.

[5]  Kelvin E. Jones,et al.  Neuronal variability: noise or part of the signal? , 2005, Nature Reviews Neuroscience.

[6]  Alex M Thomson,et al.  Physiological and morphological diversity of immunocytochemically defined parvalbumin‐ and cholecystokinin‐positive interneurones in CA1 of the adult rat hippocampus , 2002, The Journal of comparative neurology.

[7]  S. Grillner,et al.  The spinal 5-HT system contributes to the generation of fictive locomotion in lamprey , 2000, Brain Research.

[8]  J. Buchanan,et al.  Electrophysiological properties of identified classes of lamprey spinal neurons. , 1993, Journal of neurophysiology.

[9]  S. Grillner,et al.  Neural networks that co-ordinate locomotion and body orientation in lamprey , 1995, Trends in Neurosciences.

[10]  W. Regehr,et al.  Short-term synaptic plasticity. , 2002, Annual review of physiology.

[11]  R. Traub,et al.  A model of a CA3 hippocampal pyramidal neuron incorporating voltage-clamp data on intrinsic conductances. , 1991, Journal of neurophysiology.

[12]  R. C. Cannon,et al.  Distribution of spontaneous currents along the somato-dendritic axis of rat hippocampal CA1 pyramidal neurons , 2000, Neuroscience.

[13]  Ivan Soltesz,et al.  Structure of cortical microcircuit theory , 2005, The Journal of physiology.

[14]  E. Marder,et al.  Similar network activity from disparate circuit parameters , 2004, Nature Neuroscience.

[15]  J. Buchanan,et al.  Activities of spinal neurons during brain stem-dependent fictive swimming in lamprey. , 1995, Journal of neurophysiology.

[16]  S. Palay,et al.  The Fine Structure of the Nervous System: Neurons and Their Supporting Cells , 1991 .

[17]  P. Wallén,et al.  Fictive locomotion in the lamprey spinal cord in vitro compared with swimming in the intact and spinal animal. , 1984, The Journal of physiology.

[18]  I. Soltesz,et al.  Plasticity of interneuronal species diversity and parameter variance in neurological diseases , 2004, Trends in Neurosciences.

[19]  M. Frotscher,et al.  Rapid Signaling at Inhibitory Synapses in a Dentate Gyrus Interneuron Network , 2001, The Journal of Neuroscience.

[20]  S. Grillner,et al.  Substance P Modulates NMDA Responses and Causes Long-Term Protein Synthesis-Dependent Modulation of the Lamprey Locomotor Network , 1998, The Journal of Neuroscience.

[21]  S. Prescott,et al.  Gain control of firing rate by shunting inhibition: Roles of synaptic noise and dendritic saturation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Peters Rm.  Congestive Heart Failure: the Case for Decreased Variability as a Unifying Theme , 2000 .

[23]  W. Regehr,et al.  Retinogeniculate synaptic properties controlling spike number and timing in relay neurons. , 2003, Journal of neurophysiology.

[24]  P. Sterling.  Principles of Allostasis: Optimal Design, Predictive Regulation, Pathophysiology, and Rational Therapeutics. , 2004 .

[25]  A. R. Martin,et al.  Non‐linear summation of end‐plate potentials in the frog and mouse. , 1981, The Journal of physiology.

[26]  J. Clements,et al.  Unveiling synaptic plasticity: a new graphical and analytical approach , 2000, Trends in Neurosciences.

[27]  J. White,et al.  Networks of interneurons with fast and slow gamma-aminobutyric acid type A (GABAA) kinetics provide substrate for mixed gamma-theta rhythm. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[28]  H. Robinson,et al.  Determining the activation time course of synaptic AMPA receptors from openings of colocalized NMDA receptors. , 1999, Biophysical journal.

[29]  Vladimir Brezina,et al.  Cycle-to-cycle variability as an optimal behavioral strategy , 2006, Neurocomputing.

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

[31]  T. Buchman.  The community of the self , 2002, Nature.

[32]  T. Freund,et al.  Precision and Variability in Postsynaptic Target Selection of Inhibitory Cells in the Hippocampal CA3 Region , 1993, The European journal of neuroscience.

[33]  Catherine A. Collins,et al.  A Single Vesicular Glutamate Transporter Is Sufficient to Fill a Synaptic Vesicle , 2006, Neuron.

[34]  D. Parker.  Variable Properties in a Single Class of Excitatory Spinal Synapse , 2003, The Journal of Neuroscience.

[35]  B. Walmsley,et al.  Glycinergic miniature synaptic currents and receptor cluster sizes differ between spinal cord interneurons. , 1999, Journal of neurophysiology.

[36]  J. Buchanan,et al.  Activities of identified interneurons, motoneurons, and muscle fibers during fictive swimming in the lamprey and effects of reticulospinal and dorsal cell stimulation. , 1982, Journal of neurophysiology.

[37]  T. Sejnowski,et al.  Simulations of cortical pyramidal neurons synchronized by inhibitory interneurons. , 1991, Journal of neurophysiology.

[38]  H. Atwood,et al.  Quantal Size and Variation Determined by Vesicle Size in Normal and Mutant Drosophila Glutamatergic Synapses , 2002, The Journal of Neuroscience.

[39]  François Clarac,et al.  Modulation of the spinal network for locomotion by substance P in the neonatal rat , 1997, Experimental Brain Research.

[40]  I. Módy,et al.  Tonic inhibition originates from synapses close to the soma , 1995, Neuron.

[41]  J. Voipio,et al.  Long-Lasting GABA-Mediated Depolarization Evoked by High-Frequency Stimulation in Pyramidal Neurons of Rat Hippocampal Slice Is Attributable to a Network-Driven, Bicarbonate-Dependent K+ Transient , 1997, The Journal of Neuroscience.

[42]  T. Freund,et al.  Differences between Somatic and Dendritic Inhibition in the Hippocampus , 1996, Neuron.

[43]  Daniel M. Wolpert,et al.  Making smooth moves , 2022 .

[44]  Ivan Soltesz,et al.  Diversity beyond variance: modulation of firing rates and network coherence by GABAergic subpopulations , 2004, The European journal of neuroscience.

[45]  Spinal-Cord plasticity: independent and interactive effects of neuromodulator and activity-dependent plasticity. , 2000, Molecular neurobiology.

[46]  A. Reyes,et al.  Influence of dendritic conductances on the input-output properties of neurons. , 2001, Annual review of neuroscience.

[47]  Nicholas T. Carnevale,et al.  The NEURON Simulation Environment , 1997, Neural Computation.

[48]  K. Harris,et al.  Variation in the number, location and size of synaptic vesicles provides an anatomical basis for the nonuniform probability of release at hippocampal CA1 synapses , 1995, Neuropharmacology.

[49]  D. Parker,et al.  Metaplastic Facilitation and Ultrastructural Changes in Synaptic Properties Are Associated with Long-Term Modulation of the Lamprey Locomotor Network , 2004, The Journal of Neuroscience.

[50]  K. Staley,et al.  Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors , 1995, Science.

[51]  S. Grillner,et al.  Synaptically evoked membrane potential oscillations induced by substance P in lamprey motor neurons. , 2002, Journal of neurophysiology.

[52]  A. El Manira,et al.  Characterization of a high-voltage-activated IA current with a role in spike timing and locomotor pattern generation , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[53]  T. Sejnowski,et al.  Synaptic background noise controls the input/output characteristics of single cells in an in vitro model of in vivo activity , 2003, Neuroscience.

[54]  A. Destexhe,et al.  Impact of spontaneous synaptic activity on the resting properties of cat neocortical pyramidal neurons In vivo. , 1998, Journal of neurophysiology.

[55]  R. Yuste,et al.  Linear Summation of Excitatory Inputs by CA1 Pyramidal Neurons , 1999, Neuron.

[56]  Ivan Soltesz,et al.  Postsynaptic effects of GABAergic synaptic diversity: regulation of neuronal excitability by changes in IPSC variance , 2002, Neuropharmacology.

[57]  G. Buzsáki,et al.  Interneurons of the hippocampus , 1998, Hippocampus.

[58]  Xiao-Jing Wang,et al.  Bursting Neurons Signal Input Slope , 2002, The Journal of Neuroscience.

[59]  S. Grillner,et al.  A new population of neurons with crossed axons in the lamprey spinal cord , 1991, Brain Research.

[60]  P H Tiesinga,et al.  Robust gamma oscillations in networks of inhibitory hippocampal interneurons , 1999, Network.

[61]  S. Grillner,et al.  Activity-Dependent Metaplasticity of Inhibitory and Excitatory Synaptic Transmission in the Lamprey Spinal Cord Locomotor Network , 1999, The Journal of Neuroscience.

[62]  E Marder,et al.  Network Oscillations Generated by Balancing Graded Asymmetric Reciprocal Inhibition in Passive Neurons , 1999, The Journal of Neuroscience.

[63]  S Grillner,et al.  Cellular and Synaptic Modulation Underlying Substance P-Mediated Plasticity of the Lamprey Locomotor Network , 1998, The Journal of Neuroscience.

[64]  P. Wallén,et al.  The neuronal correlate of locomotion in fish , 1980, Experimental Brain Research.

[65]  Ivan Soltesz,et al.  Impact of heterogeneous perisomatic IPSC populations on pyramidal cell firing rates. , 2004, Journal of neurophysiology.

[66]  P. Somogyi,et al.  Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons , 1995, Nature.

[67]  G. Buzsáki,et al.  Gamma Oscillation by Synaptic Inhibition in a Hippocampal Interneuronal Network Model , 1996, The Journal of Neuroscience.

[68]  D. Parker.  Complexities and uncertainties of neuronal network function , 2006, Philosophical Transactions of the Royal Society B: Biological Sciences.

[69]  Arnd Roth,et al.  Submillisecond AMPA Receptor-Mediated Signaling at a Principal Neuron–Interneuron Synapse , 1997, Neuron.

[70]  C. Stevens,et al.  Synaptic noise and other sources of randomness in motoneuron interspike intervals. , 1968, Journal of neurophysiology.

[71]  H. Robinson,et al.  Postsynaptic Variability of Firing in Rat Cortical Neurons: The Roles of Input Synchronization and Synaptic NMDA Receptor Conductance , 2000, The Journal of Neuroscience.

[72]  D. Parker.  Spinal-cord plasticity , 2000, Molecular Neurobiology.

[73]  Attila Szücs,et al.  Dopamine modulation of spike dynamics in bursting neurons , 2005, The European journal of neuroscience.

[74]  A. Ewing,et al.  VMAT-Mediated Changes in Quantal Size and Vesicular Volume , 2000, The Journal of Neuroscience.

[75]  Ivan Soltesz,et al.  Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability , 2001, Nature Medicine.

[76]  R. Jung,et al.  Variability analyses suggest that supraspino–spinal interactions provide dynamic stability in motor control , 2002, Brain Research.

[77]  S. Grillner,et al.  A new class of small inhibitory interneurones in the lamprey spinal cord , 1988, Brain Research.

[78]  D. Parker.  Activity-Dependent Feedforward Inhibition Modulates Synaptic Transmission in a Spinal Locomotor Network , 2003, The Journal of Neuroscience.

[79]  G. Buzsáki,et al.  Intracellular correlates of hippocampal theta rhythm in identified pyramidal cells, granule cells, and basket cells , 1995, Hippocampus.

[80]  Ege T. Kavalali,et al.  Kinetics and regulation of fast endocytosis at hippocampal synapses , 1998, Nature.

[81]  A. Zador.  Impact of synaptic unreliability on the information transmitted by spiking neurons. , 1998, Journal of neurophysiology.

[82]  A. Graybiel,et al.  Activity of striatal neurons reflects dynamic encoding and recoding of procedural memories , 2005, Nature.

[83]  J. Buchanan.  Contributions of identifiable neurons and neuron classes to lamprey vertebrate neurobiology , 2001, Progress in Neurobiology.

[84]  Alex M. Thomson,et al.  Molecular frequency filters at central synapses , 2000, Progress in Neurobiology.

[85]  Frances S. Chance,et al.  Gain Modulation from Background Synaptic Input , 2002, Neuron.

[86]  Attila Losonczy,et al.  Cell type dependence and variability in the short‐term plasticity of EPSCs in identified mouse hippocampal interneurones , 2002, The Journal of physiology.

[87]  Tamás F Freund,et al.  Interneuron Diversity series: Rhythm and mood in perisomatic inhibition , 2003, Trends in Neurosciences.

[88]  L. Vinay,et al.  Serotonin refines the locomotor‐related alternations in the in vitro neonatal rat spinal cord , 2005, The European journal of neuroscience.

[89]  G. Westbrook,et al.  The impact of receptor desensitization on fast synaptic transmission , 1996, Trends in Neurosciences.

[90]  Golomb,et al.  Dynamics of globally coupled inhibitory neurons with heterogeneity. , 1993, Physical review. E, Statistical physics, plasmas, fluids, and related interdisciplinary topics.

[91]  D. Parker,et al.  Activity and Calcium-Dependent Mechanisms Maintain Reliable Interneuron Synaptic Transmission in a Rhythmic Neural Network , 2000, The Journal of Neuroscience.

[92]  A. Konnerth,et al.  Gamma-frequency oscillations: a neuronal population phenomenon, regulated by synaptic and intrinsic cellular processes, and inducing synaptic plasticity , 1998, Progress in Neurobiology.

[93]  F. Kuenzi,et al.  Ionic currents, transmitters and models of motor pattern generators , 1997, Current Opinion in Neurobiology.

[94]  R. Miles,et al.  How Many Subtypes of Inhibitory Cells in the Hippocampus? , 1998, Neuron.

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

[96]  Eve Marder,et al.  The dynamic clamp: artificial conductances in biological neurons , 1993, Trends in Neurosciences.

[97]  Karl M. Newell,et al.  Variability and Motor Control , 1993 .