Effect of prolonged riluzole exposure on cultured motoneurons in a mouse model of ALS

J. E. Schuster, R. Fu, T. Siddique, C. J. Heckman

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Riluzole is the only FDA-approved drug to treat amyotrophic lateral sclerosis, but its long-term effects on motoneurons are unknown. Therefore, we treated primary mouse spinal cord cultures with 2 μM riluzole for 4-9 days and then used whole cell patch clamp to record the passive and active properties of both wild-type and SOD1 G93A motoneurons. At this concentration, riluzole blocks >50% of the sodium component of a persistent inward current that plays a major role in determining motoneuron excitability. Prolonged riluzole treatment significantly decreased the amplitude of the persistent inward current. This effect was specific for SOD1 G93A motoneurons, where the amplitude decreased by 55.4%. In addition, prolonged treatment hyperpolarized the resting membrane potential as well as the voltage onset and voltage maximum of the persistent inward current (~2-3 mV in each case). These effects appeared to offset one another and resulted in no change in the firing properties. In a subset of cells, acute reapplication of 2;xM riluzole during the recording decreased repetitive firing and the persistent inward current, which is consistent with the normal effects of riluzole. The downregulation of the persistent inward current in response to prolonged riluzole administration is in contrast to the strong upregu-lation of this same current after descending neuromodulatory drive to the cord is lost following spinal injury. This dichotomy suggests that decreased activation of G protein-coupled pathways can induce up-regulation in the persistent inward current but that direct channel block is ineffective.

Original languageEnglish (US)
Pages (from-to)484-492
Number of pages9
JournalJournal of neurophysiology
Volume107
Issue number1
DOIs
StatePublished - Jan 2012

Keywords

  • Amyotrophic lateral sclerosis
  • Motoneuron excitability
  • Superoxide dismutase 1

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology

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