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      Reduced Hyperpolarization-Activated Current Contributes to Enhanced Intrinsic Excitability in Cultured Hippocampal Neurons from PrP −/− Mice

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          Abstract

          Genetic ablation of cellular prion protein (PrP C) has been linked to increased neuronal excitability and synaptic activity in the hippocampus. We have previously shown that synaptic activity in hippocampi of PrP-null mice is increased due to enhanced N-methyl-D-aspartate receptor (NMDAR) function. Here, we focused on the effect of PRNP gene knock-out (KO) on intrinsic neuronal excitability, and in particular, the underlying ionic mechanism in hippocampal neurons cultured from P0 mouse pups. We found that the absence of PrP C profoundly affected the firing properties of cultured hippocampal neurons in the presence of synaptic blockers. The membrane impedance was greater in PrP-null neurons, and this difference was abolished by the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker ZD7288 (100 μM). HCN channel activity appeared to be functionally regulated by PrP C. The amplitude of voltage sag, a characteristic of activating HCN channel current ( I h), was decreased in null mice. Moreover, I h peak current was reduced, along with a hyperpolarizing shift in activation gating and slower kinetics. However, neither HCN1 nor HCN2 formed a biochemical complex with PrP C. These results suggest that the absence of PrP downregulates the activity of HCN channels through activation of a cell signaling pathway rather than through direct interactions. This in turn contributes to an increase in membrane impedance to potentiate neuronal excitability.

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          Hyperpolarization-activated cation channels: from genes to function.

          Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels comprise a small subfamily of proteins within the superfamily of pore-loop cation channels. In mammals, the HCN channel family comprises four members (HCN1-4) that are expressed in heart and nervous system. The current produced by HCN channels has been known as I(h) (or I(f) or I(q)). I(h) has also been designated as pacemaker current, because it plays a key role in controlling rhythmic activity of cardiac pacemaker cells and spontaneously firing neurons. Extensive studies over the last decade have provided convincing evidence that I(h) is also involved in a number of basic physiological processes that are not directly associated with rhythmicity. Examples for these non-pacemaking functions of I(h) are the determination of the resting membrane potential, dendritic integration, synaptic transmission, and learning. In this review we summarize recent insights into the structure, function, and cellular regulation of HCN channels. We also discuss in detail the different aspects of HCN channel physiology in the heart and nervous system. To this end, evidence on the role of individual HCN channel types arising from the analysis of HCN knockout mouse models is discussed. Finally, we provide an overview of the impact of HCN channels on the pathogenesis of several diseases and discuss recent attempts to establish HCN channels as drug targets.
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            Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein.

            PrPC is a host protein anchored to the outer surface of neurons and to a lesser extent of lymphocytes and other cells. The transmissible agent (prion) responsible for scrapie is believed to be a modified form of PrPC. Mice homozygous for disrupted PrP genes have been generated. Surprisingly, they develop and behave normally for at least seven months, and no immunological defects are apparent. It is now feasible to determine whether mice devoid of PrPC can propagate prions and are susceptible to scrapie pathogenesis.
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              Hyperpolarization-activated cation currents: from molecules to physiological function.

              Hyperpolarization-activated cation currents, termed If, Ih, or Iq, were initially discovered in heart and nerve cells over 20 years ago. These currents contribute to a wide range of physiological functions, including cardiac and neuronal pacemaker activity, the setting of resting potentials, input conductance and length constants, and dendritic integration. The hyperpolarization-activated, cation nonselective (HCN) gene family encodes the channels that underlie Ih. Here we review the relation between the biophysical properties of recombinant HCN channels and the pattern of HCN mRNA expression with the properties of native Ih in neurons and cardiac muscle. Moreover, we consider selected examples of the expanding physiological functions of Ih with a view toward understanding how the properties of HCN channels contribute to these diverse functional roles.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                24 March 2016
                2016
                : 10
                : 74
                Affiliations
                [1]Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary Calgary, AB, Canada
                Author notes

                Edited by: Marco Martina, Northwestern University, USA

                Reviewed by: Stephen Ferguson, University of Western Ontario, Canada; Christian Hansel, University of Chicago, USA

                *Correspondence: Gerald W. Zamponi zamponi@ 123456ucalgary.ca
                Article
                10.3389/fncel.2016.00074
                4805597
                27047338
                d3504573-f539-4f8f-9035-415640c59979
                Copyright © 2016 Fan, Stemkowski, Gandini, Black, Zhang, Souza, Chen and Zamponi.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 16 October 2015
                : 10 March 2016
                Page count
                Figures: 5, Tables: 1, Equations: 3, References: 50, Pages: 10, Words: 7426
                Funding
                Funded by: Canadian Institutes of Health Research 10.13039/501100000024
                Categories
                Neuroscience
                Original Research

                Neurosciences
                cellular prion protein,hcn,excitability,ih,hippocampus
                Neurosciences
                cellular prion protein, hcn, excitability, ih, hippocampus

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