Single Ih Channels in Pyramidal Neuron Dendrites: Properties, Distribution, and Impact on Action Potential Output

The hyperpolarization-activated cation current (Ih) plays an important role in regulating neuronal excitability, yet its native single-channel properties in the brain are essentially unknown. Here we use variance-mean analysis to study the properties of single Ih channels in the apical dendrites of cortical layer 5 pyramidal neurons in vitro. In these neurons, we find that Ih channels have an average unitary conductance of 680 ± 30 fS (n = 18). Spectral analysis of simulated and native Ih channels showed that there is little or no channel flicker below 5 kHz. In contrast to the uniformly distributed single-channel conductance, Ih channel number increases exponentially with distance, reaching densities as high as ∼550 channels/μm2 at distal dendritic sites. These high channel densities generate significant membrane voltage noise. By incorporating a stochastic model of Ih single-channel gating into a morphologically realistic model of a layer 5 neuron, we show that this channel noise is higher in distal dendritic compartments and increased threefold with a 10-fold increased single-channel conductance (6.8 pS) but constant Ih current density. In addition, we demonstrate that voltage fluctuations attributable to stochastic Ih channel gating impact on action potential output, with greater spike-timing precision in models with the experimentally determined single-channel conductance. These data suggest that, in the face of high current densities, the small single-channel conductance of Ih is critical for maintaining the fidelity of action potential output.

[1]  B. Hille.  Ionic channels in excitable membranes. Current problems and biophysical approaches. , 1978, Biophysical journal.

[2]  H. Brown,et al.  How does adrenaline accelerate the heart? , 1979, Nature.

[3]  F. Sigworth.  The variance of sodium current fluctuations at the node of Ranvier , 1980, The Journal of physiology.

[4]  F. Conti,et al.  Conductance fluctuations from the inactivation process of sodium channels in myelinated nerve fibres * , 1980, The Journal of physiology.

[5]  Louis J. DeFelice,et al.  Introduction to membrane noise , 1981 .

[6]  Paul R. Adams,et al.  Voltage-clamp analysis of muscarinic excitation in hippocampal neurons , 1982, Brain Research.

[7]  B. Hille.  Ionic channels of excitable membranes , 2001 .

[8]  D DiFrancesco,et al.  Characterization of the pace‐maker current kinetics in calf Purkinje fibres. , 1984, The Journal of physiology.

[9]  Dario DiFrancesco,et al.  Characterization of single pacemaker channels in cardiac sino-atrial node cells , 1986, Nature.

[10]  S. Hestrin,et al.  The properties and function of inward rectification in rod photoreceptors of the tiger salamander. , 1987, The Journal of physiology.

[11]  F. A. Seiler,et al.  Numerical Recipes in C: The Art of Scientific Computing , 1989 .

[12]  D. McCormick,et al.  Properties of a hyperpolarization‐activated cation current and its role in rhythmic oscillation in thalamic relay neurones. , 1990, The Journal of physiology.

[13]  A. Hodgkin,et al.  A quantitative description of membrane current and its application to conduction and excitation in nerve , 1990 .

[14]  I. Briggs,et al.  Inhibitory actions of ZENECA ZD7288 on whole‐cell hyperpolarization activated inward current (If) in guinea‐pig dissociated sinoatrial node cells , 1993, British journal of pharmacology.

[15]  Wiesenfeld,et al.  Stochastic resonance on a circle. , 1994, Physical review letters.

[16]  Hyperpolarization-activated Na(+)-K+ current (Ih) in neocortical neurons is blocked by external proteolysis and internal TEA. , 1994, Journal of neurophysiology.

[17]  B. Sakmann,et al.  Active propagation of somatic action potentials into neocortical pyramidal cell dendrites , 1994, Nature.

[18]  Kurt Wiesenfeld,et al.  Stochastic resonance and the benefits of noise: from ice ages to crayfish and SQUIDs , 1995, Nature.

[19]  J. Ruppersberg.  Ion Channels in Excitable Membranes , 1996 .

[20]  M. Häusser,et al.  Estimating the Time Course of the Excitatory Synaptic Conductance in Neocortical Pyramidal Cells Using a Novel Voltage Jump Method , 1997, The Journal of Neuroscience.

[21]  J. Magee.  Dendritic Hyperpolarization-Activated Currents Modify the Integrative Properties of Hippocampal CA1 Pyramidal Neurons , 1998, The Journal of Neuroscience.

[22]  Eric R Kandel,et al.  Identification of a Gene Encoding a Hyperpolarization-Activated Pacemaker Channel of Brain , 1998, Cell.

[23]  Idan Segev,et al.  Ion Channel Stochasticity May Be Critical in Determining the Reliability and Precision of Spike Timing , 1998, Neural Computation.

[24]  M. Biel,et al.  A family of hyperpolarization-activated mammalian cation channels , 1998, Nature.

[25]  N. Spruston,et al.  Determinants of Voltage Attenuation in Neocortical Pyramidal Neuron Dendrites , 1998, The Journal of Neuroscience.

[26]  B. Santoro,et al.  The HCN Gene Family: Molecular Basis of the Hyperpolarization‐Activated Pacemaker Channels , 1999, Annals of the New York Academy of Sciences.

[27]  W. Stacey,et al.  Stochastic resonance improves signal detection in hippocampal CA1 neurons. , 2000, Journal of Neurophysiology.

[28]  Nicholas T. Carnevale,et al.  Expanding NEURON's Repertoire of Mechanisms with NMODL , 2000, Neural Computation.

[29]  J. White,et al.  Channel noise in neurons , 2000, Trends in Neurosciences.

[30]  G. Stuart,et al.  Site independence of EPSP time course is mediated by dendritic I(h) in neocortical pyramidal neurons. , 2000, Journal of neurophysiology.

[31]  M. Larkum,et al.  High I(h) channel density in the distal apical dendrite of layer V pyramidal cells increases bidirectional attenuation of EPSPs. , 2001, Journal of neurophysiology.

[32]  S. Siegelbaum,et al.  Molecular mechanism of cAMP modulation of HCN pacemaker channels , 2001, Nature.

[33]  Simon B. Laughlin,et al.  Energy-Efficient Coding with Discrete Stochastic Events , 2002, Neural Computation.

[34]  Martin Biel,et al.  Cardiac HCN channels: structure, function, and modulation. , 2002, Trends in cardiovascular medicine.

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

[36]  Gábor Tamás,et al.  Polarized and compartment-dependent distribution of HCN1 in pyramidal cell dendrites , 2002, Nature Neuroscience.

[37]  Osvaldo Alvarez,et al.  Counting channels: a tutorial guide on ion channel fluctuation analysis. , 2002, Advances in physiology education.

[38]  G. Stuart,et al.  Excitatory Actions of GABA in the Cortex , 2003, Neuron.

[39]  G. Stuart,et al.  Voltage- and Site-Dependent Control of the Somatic Impact of Dendritic IPSPs , 2003, The Journal of Neuroscience.

[40]  S. Siegelbaum,et al.  Hyperpolarization-activated cation currents: from molecules to physiological function. , 2003, Annual review of physiology.

[41]  Terrence J Sejnowski,et al.  Communication in Neuronal Networks , 2003, Science.

[42]  Rich Olson,et al.  Structural basis for modulation and agonist specificity of HCN pacemaker channels , 2003, Nature.

[43]  Andreas T. Schaefer,et al.  Coincidence detection in pyramidal neurons is tuned by their dendritic branching pattern. , 2003, Journal of neurophysiology.

[44]  A G Hawkes,et al.  The quality of maximum likelihood estimates of ion channel rate constants , 2003, The Journal of physiology.

[45]  A. Destexhe,et al.  The high-conductance state of neocortical neurons in vivo , 2003, Nature Reviews Neuroscience.

[46]  D. DiFrancesco,et al.  Interaction of the Pacemaker Channel HCN1 with Filamin A* , 2004, Journal of Biological Chemistry.

[47]  R. Shigemoto,et al.  Immunohistochemical localization of Ih channel subunits, HCN1–4, in the rat brain , 2004, The Journal of comparative neurology.

[48]  Christof Koch,et al.  Intrinsic Noise in Cultured Hippocampal Neurons: Experiment and Modeling , 2004, The Journal of Neuroscience.

[49]  S. Siegelbaum,et al.  Regulation of HCN Channel Surface Expression by a Novel C-Terminal Protein-Protein Interaction , 2004, The Journal of Neuroscience.

[50]  T. Baram,et al.  Single channel properties of hyperpolarization‐activated cation currents in acutely dissociated rat hippocampal neurones , 2005, The Journal of physiology.

[51]  Stefan Herzig,et al.  Single-Channel Properties Support a Potential Contribution of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels and If to Cardiac Arrhythmias , 2005, Circulation.

[52]  Christof Koch,et al.  Subthreshold voltage noise of rat neocortical pyramidal neurones , 2005, The Journal of physiology.

[53]  Peter Jonas,et al.  Presynaptic Action Potential Amplification by Voltage-Gated Na+ Channels in Hippocampal Mossy Fiber Boutons , 2005, Neuron.

[54]  Alan D Dorval,et al.  Channel Noise is Essential for Perithreshold Oscillations in Entorhinal Stellate Neurons , 2005, The Journal of Neuroscience.

[55]  S. Laughlin,et al.  Ion-Channel Noise Places Limits on the Miniaturization of the Brain’s Wiring , 2005, Current Biology.

[56]  W. N. Zagotta,et al.  The carboxyl-terminal region of cyclic nucleotide-modulated channels is a gating ring, not a permeation path. , 2005, Proceedings of the National Academy of Sciences of the United States of America.