title: Downregulation of Spermine Augments Dendritic Persistent Sodium Currents and Synaptic Integration after Status Epilepticus.
abstract: Dendritic voltage-gated ion channels profoundly shape the integrative properties of neuronal dendrites. In epilepsy, numerous changes in dendritic ion channels have been described, all of them due to either their altered transcription or phosphorylation. In pilocarpine-treated chronically epileptic rats, we describe a novel mechanism that causes an increased proximal dendritic persistent Na(+) current (INaP). We demonstrate using a combination of electrophysiology and molecular approaches that the upregulation of dendritic INaP is due to a relief from polyamine-dependent inhibition. The polyamine deficit in hippocampal neurons is likely caused by an upregulation of the degrading enzyme spermidine/spermine acetyltransferase. Multiphoton glutamate uncaging experiments revealed that the increase in dendritic INaP causes augmented dendritic summation of excitatory inputs. These results establish a novel post-transcriptional modification of ion channels in chronic epilepsy and may provide a novel avenue for treatment of temporal lobe epilepsy.
  
  
  CONCLUSIONS
  In this paper, we describe a novel mechanism that causes increased dendritic persistent Na(+) current. We demonstrate using a combination of electrophysiology and molecular approaches that the upregulation of persistent Na(+) currents is due to a relief from polyamine-dependent inhibition. The polyamine deficit in hippocampal neurons is likely caused by an upregulation of the degrading enzyme spermidine/spermine acetyltransferase. Multiphoton glutamate uncaging experiments revealed that the increase in dendritic persistent Na current causes augmented dendritic summation of excitatory inputs. We believe that these results establish a novel post-transcriptional modification of ion channels in chronic epilepsy.
authors.affiliation: Laboratory for Experimental Epileptology and Cognition Research, Department of Epileptology, and.
authors.forename: Michel
authors.initials: M
authors.lastname: Royeck
authors.affiliation: Laboratory for Experimental Epileptology and Cognition Research, Department of Epileptology, and.
authors.forename: Tony
authors.initials: T
authors.lastname: Kelly
authors.affiliation: Laboratory for Experimental Epileptology and Cognition Research, Department of Epileptology, and.
authors.forename: Thoralf
authors.initials: T
authors.lastname: Opitz
authors.affiliation: Institute of Molecular Psychiatry, University of Bonn, D-53105 Bonn, Germany.
authors.forename: David-Marian
authors.initials: DM
authors.lastname: Otte
authors.affiliation: Department of Molecular Sensory Systems, Center of Advanced European Studies and Research, D-53175 Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rennhack
authors.affiliation: Department of Neuropathology, University of Bonn, D-53105 Bonn, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Woitecki
authors.affiliation: Department of Neuropathology, University of Bonn, D-53105 Bonn, Germany.
authors.forename: Julika
authors.initials: J
authors.lastname: Pitsch
authors.affiliation: Department of Neuropathology, University of Bonn, D-53105 Bonn, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Becker
authors.affiliation: Department of Neuropathology, University of Bonn, D-53105 Bonn, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schoch
authors.affiliation: Department of Molecular Sensory Systems, Center of Advanced European Studies and Research, D-53175 Bonn, Germany.
authors.forename: Ulrich Benjamin
authors.initials: UB
authors.lastname: Kaupp
authors.affiliation: Department of Medical Neurobiology, IMRIC, Hebrew University-Hadassah School of Medicine, Jerusalem 91120, Israel, and.
authors.forename: Yoel
authors.identifier: http://orcid.org/0000-0002-4794-1436
authors.initials: Y
authors.lastname: Yaari
authors.affiliation: Institute of Molecular Psychiatry, University of Bonn, D-53105 Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.affiliation: Laboratory for Experimental Epileptology and Cognition Research, Department of Epileptology, and Deutsches Zentrum für Neurodegenerative Erkrankungen e.V., 53175 Bonn, Germany Heinz.beck@ukb.uni-bonn.de.
authors.forename: Heinz
authors.initials: H
authors.lastname: Beck
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000473:pathology*; D003712:Dendrites / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018721:Muscarinic Agonists / Q000633:toxicity; D010862:Pilocarpine / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D013096:Spermine / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology*; D016708:Synaptophysin / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D018721:Muscarinic Agonists; D012333:RNA, Messenger; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D016708:Synaptophysin; D010862:Pilocarpine; D013096:Spermine; D013779:Tetrodotoxin
keywords: epilepsy; persistent sodium current; polyamines; sodium channels; spermine; synaptic integration