A Behavioral Role for Dendritic Integration HCN1 Channels Constrain Spatial Memory and Plasticity at Inputs to Distal Dendrites of CA1 Pyramidal Neurons

The importance of long-term synaptic plasticity as a cellular substrate for learning and memory is well established. By contrast, little is known about how learning and memory are regulated by voltage-gated ion channels that integrate synaptic information. We investigated this question using mice with general or forebrain-restricted knockout of the HCN1 gene, which we find encodes a major component of the hyperpolarization-activated inward current (Ih) and is an important determinant of dendritic integration in hippocampal CA1 pyramidal cells. Deletion of HCN1 from forebrain neurons enhances hippocampal-dependent learning and memory, augments the power of theta oscillations, and enhances long-term potentiation (LTP) at the direct perforant path input to the distal dendrites of CA1 pyramidal neurons, but has little effect on LTP at the more proximal Schaffer collateral inputs. We suggest that HCN1 channels constrain learning and memory by regulating dendritic integration of distal synaptic inputs to pyramidal cells.

[1]  L. Voronin,et al.  Long-term potentiation in the hippocampus , 1983, Neuroscience.

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

[3]  窪田 美恵.  Intact LTP and fear memory but impaired spatial memory in mice lacking Ca[v]2.3 (α1E) channel , 2001 .

[4]  H. Markram,et al.  Regulation of Synaptic Efficacy by Coincidence of Postsynaptic APs and EPSPs , 1997, Science.

[5]  J. Sanes,et al.  Can molecules explain long-term potentiation? , 1999, Nature Neuroscience.

[6]  M. Witter,et al.  Anatomical Organization of the Parahippocampal‐Hippocampal Network , 2000, Annals of the New York Academy of Sciences.

[7]  J. Storm,et al.  Two forms of electrical resonance at theta frequencies, generated by M‐current, h‐current and persistent Na+ current in rat hippocampal pyramidal cells , 2002, The Journal of physiology.

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

[9]  E. Kandel,et al.  A genetic test of the effects of mutations in PKA on mossy fiber ltp and its relation to spatial and contextual learning , 1995, Cell.

[10]  J. Lisman.  Relating Hippocampal Circuitry to Function Recall of Memory Sequences by Reciprocal Dentate–CA3 Interactions , 1999, Neuron.

[11]  G. Buzsáki.  Theta Oscillations in the Hippocampus , 2002, Neuron.

[12]  G. Buzsáki,et al.  Hippocampal network patterns of activity in the mouse , 2003, Neuroscience.

[13]  C. McBain,et al.  The hyperpolarization‐activated current (Ih) and its contribution to pacemaker activity in rat CA1 hippocampal stratum oriens‐alveus interneurones. , 1996, The Journal of physiology.

[14]  W. Levy,et al.  Long-term potentiation of perforant path synapses in hippocampll CA1 in vitro , 1993, Brain Research.

[15]  Eric R. Kandel,et al.  Inducible and Reversible Enhancement of Learning, Memory, and Long-Term Potentiation by Genetic Inhibition of Calcineurin , 2001, Cell.

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

[17]  E. Kandel,et al.  Memory suppressor genes: inhibitory constraints on the storage of long-term memory. , 1998, Science.

[18]  A Routtenberg,et al.  Enhanced learning after genetic overexpression of a brain growth protein. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Knut Holthoff,et al.  Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2 , 2003, The EMBO journal.

[20]  Ryen W. White,et al.  Introduction , 2006, Commun. ACM.

[21]  G Buzsáki,et al.  Sustained activation of hippocampal pyramidal cells by ‘space clamping’ in a running wheel , 1999, The European journal of neuroscience.

[22]  J. Magee.  Dendritic lh normalizes temporal summation in hippocampal CA1 neurons. , 1999, Nature neuroscience.

[23]  J. Lisman,et al.  Contribution of Ih and GABAB to synaptically induced afterhyperpolarizations in CA1: a brake on the NMDA response. , 2004, Journal of neurophysiology.

[24]  T. Bliss,et al.  Lamellar organization of hippocampal excitatory pathways , 1971, Experimental Brain Research.

[25]  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.

[26]  Richard G M Morris,et al.  Introduction. Long-term potentiation and structure of the issue. , 2003, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[27]  D. Johnston,et al.  A Synaptically Controlled, Associative Signal for Hebbian Plasticity in Hippocampal Neurons , 1997, Science.

[28]  E. Shimizu,et al.  Genetic enhancement of learning and memory in mice , 1999, Nature.

[29]  H. Saegusa,et al.  Intact LTP and fear memory but impaired spatial memory in mice lacking Ca(v)2.3 (alpha(IE)) channel. , 2001, Biochemical and biophysical research communications.

[30]  M. Alreja,et al.  Hippocampal theta rhythm is reduced by suppression of the H‐current in septohippocampal GABAergic neurons , 2004, The European journal of neuroscience.

[31]  Menno P. Witter,et al.  Place Cells and Place Recognition Maintained by Direct Entorhinal-Hippocampal Circuitry , 2002, Science.

[32]  Nace L. Golding,et al.  Dendritic spikes as a mechanism for cooperative long-term potentiation , 2002, Nature.

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

[34]  S. Siegelbaum,et al.  Molecular and Functional Heterogeneity of Hyperpolarization-Activated Pacemaker Channels in the Mouse CNS , 2000, The Journal of Neuroscience.

[35]  T. Teyler,et al.  Long-term potentiation. , 1987, Annual review of neuroscience.

[36]  Kenneth D Harris,et al.  Selective Impairment of Hippocampal Gamma Oscillations in Connexin-36 Knock-Out Mouse In Vivo , 2003, The Journal of Neuroscience.

[37]  T. Bliss,et al.  A synaptic model of memory: long-term potentiation in the hippocampus , 1993, Nature.

[38]  A. Hoffman,et al.  Contribution of the hyperpolarization-activated current (I(h)) to membrane potential and GABA release in hippocampal interneurons. , 2001, Journal of neurophysiology.

[39]  E. Kandel,et al.  Interactive cloning with the SH3 domain of N-src identifies a new brain specific ion channel protein, with homology to eag and cyclic nucleotide-gated channels. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[40]  S. Siegelbaum,et al.  Properties of Hyperpolarization-Activated Pacemaker Current Defined by Coassembly of Hcn1 and Hcn2 Subunits and Basal Modulation by Cyclic Nucleotide , 2001, The Journal of general physiology.

[41]  Matthew F. Nolan,et al.  The Hyperpolarization-Activated HCN1 Channel Is Important for Motor Learning and Neuronal Integration by Cerebellar Purkinje Cells , 2003, Cell.

[42]  R Hen,et al.  5-HT1B Receptor Knock-Out Mice Exhibit Increased Exploratory Activity and Enhanced Spatial Memory Performance in the Morris Water Maze , 1999, The Journal of Neuroscience.

[43]  G. Buzsáki,et al.  Theta oscillations in somata and dendrites of hippocampal pyramidal cells in vivo: Activity‐dependent phase‐precession of action potentials , 1998, Hippocampus.

[44]  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.

[45]  E. Schuman,et al.  Direct cortical input modulates plasticity and spiking in CA1 pyramidal neurons , 2002, Nature.

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

[47]  F. G. Pike,et al.  Distinct frequency preferences of different types of rat hippocampal neurones in response to oscillatory input currents , 2000, The Journal of physiology.

[48]  Jeffrey C. Magee,et al.  Dendritic I h normalizes temporal summation in hippocampal CA 1 neurons , 1999 .

[49]  S. Capaccioli,et al.  Reversible antisense inhibition of Shaker-like Kv1.1 potassium channel expression impairs associative memory in mouse and rat. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[50]  J. Wess,et al.  Muscarinic Induction of Hippocampal Gamma Oscillations Requires Coupling of the M1 Receptor to Two Mixed Cation Currents , 2002, Neuron.

[51]  J. Tytgat,et al.  Functional Heteromerization of HCN1 and HCN2 Pacemaker Channels* , 2001, The Journal of Biological Chemistry.

[52]  E. Kandel,et al.  Cognitive Neuroscience and the Study of Memory , 1998, Neuron.

[53]  J. Lisman,et al.  Pathway-Specific Properties of AMPA and NMDA-Mediated Transmission in CA1 Hippocampal Pyramidal Cells , 2002, The Journal of Neuroscience.

[54]  Mu-ming Poo,et al.  Bidirectional Changes in Spatial Dendritic Integration Accompanying Long-Term Synaptic Modifications , 2003, Neuron.

[55]  D. DiFrancesco,et al.  Action of the hyperpolarization-activated current (Ih) blocker ZD 7288 in hippocampal CA1 neurons , 1997, Pflügers Archiv.

[56]  Subthreshold frequency selectivity in avian auditory thalamus. , 1994, Journal of neurophysiology.

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