Downregulation of Spermine Augments Dendritic Persistent Sodium Currents and Synaptic Integration After Status Epilepticus

J Neurosci. 2015 Nov 18;35(46):15240-53. doi: 10.1523/JNEUROSCI.0493-15.2015.

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.

Significance statement: 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.

Keywords: epilepsy; persistent sodium current; polyamines; sodium channels; spermine; synaptic integration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / genetics
  • Analysis of Variance
  • Animals
  • CA1 Region, Hippocampal / pathology*
  • Dendrites / drug effects
  • Dendrites / physiology*
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Down-Regulation / physiology*
  • Humans
  • In Vitro Techniques
  • Male
  • Muscarinic Agonists / toxicity
  • Pilocarpine / toxicity
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Sodium Channel Blockers / pharmacology
  • Sodium Channels / drug effects
  • Sodium Channels / physiology*
  • Spermine / metabolism*
  • Statistics, Nonparametric
  • Status Epilepticus / chemically induced
  • Status Epilepticus / pathology*
  • Synaptophysin / metabolism
  • Tetrodotoxin / pharmacology
  • Up-Regulation / drug effects
  • Up-Regulation / physiology

Substances

  • Muscarinic Agonists
  • RNA, Messenger
  • Sodium Channel Blockers
  • Sodium Channels
  • Synaptophysin
  • Pilocarpine
  • Spermine
  • Tetrodotoxin