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

• DOI: 10.1523/jneurosci.0493-15.2015
• Publication Date: 2015-11-19T21:12:25Z
• Authors: Michel Royeck; Tony Kelly; Thoralf Opitz; David-Marian Otte; Andreas Rennhack; Anne Woitecki; Julika Pitsch; Albert Becker; Susanne Schoch; Ulrich Benjamin K...; Yoel Yaari; Andreas Zimmer; Heinz Beck
• Keywords: Male; 0301 basic medicine; toxicity [Muscarinic Agonists]; pharmacology [Sodium Channel Blockers]; Synaptophysin; Action Potentials; Down-Regulation; genetics [Action Potentials]; Tetrodotoxin; In Vitro Techniques; Muscarinic Agonists; metabolism [RNA, Messenger]; toxicity [Pilocarpine]; Sodium Channels; Statistics, Nonparametric; 03 medical and health sciences; Status Epilepticus; drug effects [Dendrites]; physiology [Sodium Channels]; pharmacology [Tetrodotoxin]; Animals; Humans; ddc:610; RNA, Messenger; Rats, Wistar; drug effects [Sodium Channels]; CA1 Region, Hippocampal; Analysis of Variance; drug effects [Action Potentials]; metabolism [Synaptophysin]; Pilocarpine; pathology [CA1 Region, Hippocampal]; physiology [Dendrites]; Dendrites; metabolism [Spermine]; drug effects [Up-Regulation]; physiology [Up-Regulation]; Rats; Disease Models, Animal; physiology [Down-Regulation]; drug effects [Down-Regulation]; pathology [Status Epilepticus]; Spermine; chemically induced [Status Epilepticus]; Sodium Channel Blockers

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 dendriticINaPis 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 dendriticINaPcauses 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 STATEMENTIn 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.