A Behavioral Role for Dendritic IntegrationHCN1 Channels Constrain Spatial Memory and Plasticity at Inputs to Distal Dendrites of CA1 Pyramidal Neurons

Center for Neurobiology and Behavior, Columbia University, New York, NY 10032, USA.
Cell (Impact Factor: 32.24). 12/2004; 119(5):719-32. DOI: 10.1016/j.cell.2004.11.020
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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.

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Available from: Joshua T Dudman, Sep 30, 2015
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    • "We flanked exon II of the CPEB3 gene and the neomycin selection marker with two loxP sites by homologous recombination in embryonic stem (ES) cells (Figure 2A). To generate conditional lines that have both spatial and temporal patterns of CPEB3 recombination, we crossed the CPEB3 floxed mice to CaMKII-Cre transgenic mice (Nolan et al., 2004). In situ hybridization revealed an almost complete ablation of CPEB3 mRNA expression in the hippocampus and cortex in the CPEB3 CKO mice, compared with wild-type (WT) control mice (Figure 2B). "
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    ABSTRACT: Consolidation of long-term memories depends on de novo protein synthesis. Several translational regulators have been identified, and their contribution to the formation of memory has been assessed in the mouse hippocampus. None of them, however, has been implicated in the persistence of memory. Although persistence is a key feature of long-term memory, how this occurs, despite the rapid turnover of its molecular substrates, is poorly understood. Here we find that both memory storage and its underlying synaptic plasticity are mediated by the increase in level and in the aggregation of the prion-like translational regulator CPEB3 (cytoplasmic polyadenylation element-binding protein). Genetic ablation of CPEB3 impairs the maintenance of both hippocampal long-term potentiation and hippocampus-dependent spatial memory. We propose a model whereby persistence of long-term memory results from the assembly of CPEB3 into aggregates. These aggregates serve as functional prions and regulate local protein synthesis necessary for the maintenance of long-term memory. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 06/2015; 86(6). DOI:10.1016/j.neuron.2015.05.021 · 15.05 Impact Factor
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    • "Whereas many place cell studies have focused on defining patterns of plasticity and stability associated with these spatial representations, relatively little is known about the underlying molecular mechanisms. Some of the receptors and transcription factors known to be involved in long-term potentiation and memory consolidation have been linked to place cell encoding and stability, which include hyperpolarizationactivated cyclic nucleotide-gated channels (Hussaini et al., 2011; Nolan et al., 2004), NMDA receptors (Ekstrom et al., 2001; Kentros et al., 1998; Nakazawa et al., 2003), and zif268 (Renaudineau et al., 2009). Together, these studies highlight the importance of cellsignaling cascades and gene activity to place cell function; but epigenetic factors underlying transcriptional regulation and associated gene expression patterns in spatial cognition remain unclear. "
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    ABSTRACT: Epigenetic mechanisms including altered DNA methylation are critical for altered gene transcription subserving synaptic plasticity and the retention of learned behavior. Here we tested the idea that one role for activity-dependent altered DNA methylation is stabilization of cognition-associated hippocampal place cell firing in response to novel place learning. We observed that a behavioral protocol (spatial exploration of a novel environment) known to induce hippocampal place cell remapping resulted in alterations of hippocampal Bdnf DNA methylation. Further studies using neurophysiological in vivo single unit recordings revealed that pharmacological manipulations of DNA methylation decreased long-term but not short-term place field stability. Together our data highlight a role for DNA methylation in regulating neurophysiological spatial representation and memory formation.
    03/2015; 101. DOI:10.1016/j.nepig.2015.03.001
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    • "Hyperpolarization-activated cation current (Ih) is conducted by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and has been described in multiple neuronal types, such as thalamic neurons, hippocampal CA1 pyramidal neurons, primary afferent neurons, and spinal dorsal horn neurons (Doan et al., 2004; Gao et al., 2012; Ingram and Williams, 1996; McCormick and Pape, 1990; Nolan et al., 2004; Rivera-Arconada et al., 2013). It is a mixed inward cationic current carried by Na + and K + . "
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    ABSTRACT: Minocycline is a widely used glial activation inhibitor that could suppress pain-related behaviors in a number of different pain animal models, yet, its analgesic mechanisms are not fully understood. Hyperpolarization-activated cation channel-induced Ih current plays an important role in neuronal excitability and pathological pain. In this study, we investigated the possible effect of minocycline on Ih of substantia gelatinosa neuron in superficial spinal dorsal horn by using whole-cell patch-clamp recording. We found that extracellular minocycline rapidly decreases Ih amplitude in a reversible and concentration-dependent manner (IC50 = 41 μM). By contrast, intracellular minocycline had no effect. Minocycline-induced inhibition of Ih was not affected by Na(+) channel blocker tetrodotoxin, glutamate-receptor antagonists (CNQX and D-APV), GABAA receptor antagonist (bicuculine methiodide), or glycine receptor antagonist (strychnine). Minocycline also caused a negative shift in the activation curve of Ih, but did not alter the reversal potential. Moreover, minocycline slowed down the inter-spike depolarizing slope and produced a robust decrease in the rate of action potential firing. Together, these results illustrate a novel cellular mechanism underlying minocycline's analgesic effect by inhibiting Ih currents of spinal dorsal horn neurons. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 03/2015; 19(8). DOI:10.1016/j.neuropharm.2015.03.001 · 5.11 Impact Factor
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