Pre- and postsynaptic mechanisms underlying inhibition of hypoglossal motor neuron excitability by riluzole

Bellingham, Mark C. (2013) Pre- and postsynaptic mechanisms underlying inhibition of hypoglossal motor neuron excitability by riluzole. Journal of Neurophysiology, 110 5: 1047-1061. doi:10.1152/jn.00587.2012

Author Bellingham, Mark C.
Title Pre- and postsynaptic mechanisms underlying inhibition of hypoglossal motor neuron excitability by riluzole
Journal name Journal of Neurophysiology   Check publisher's open access policy
ISSN 0022-3077
Publication date 2013-09-01
Sub-type Article (original research)
DOI 10.1152/jn.00587.2012
Volume 110
Issue 5
Start page 1047
End page 1061
Total pages 15
Place of publication Bethesda, MD, United States
Publisher American Physiological Society
Collection year 2014
Language eng
Formatted abstract
Riluzole is the sole treatment for amyotrophic lateral sclerosis (ALS), but its therapeutically relevant actions on motor neurons are not well defined. Whole cell patch-clamp recordings were made from hypoglossal motor neurons (HMs, n = 25) in brain stem slices from 10- to 23-day-old rats anesthetized with pentobarbital sodium to investigate the hypothesis that riluzole inhibits HMs by multiple mechanisms. Riluzole (20 μM) hyperpolarized HMs by decreasing an inward current, inhibited voltage-gated persistent Na+ and Ca2+ currents activated by slow voltage ramps, and negatively shifted activation of the hyperpolarization-activated cationic current (IH). Repetitive firing of HMs was strongly inhibited by riluzole, which also increased action potential threshold voltage and rheobase and decreased amplitude and maximum rise slope but did not alter the maximal afterhyperpolarization amplitude or decay time constant. HM rheobase was inversely correlated with persistent Na+ current density. Glutamatergic synaptic transmission was inhibited by riluzole by both pre- and postsynaptic effects. Riluzole decreased activity-dependent glutamate release, as shown by decreased amplitude of evoked and spontaneous excitatory postsynaptic currents (EPSCs), decreased paired-pulse ratio, and decreased spontaneous, but not miniature, EPSC frequency. However, riluzole also decreased miniature EPSC amplitude and the inward current evoked by local application of glutamate onto HMs, suggesting a reduction of postsynaptic glutamate receptor sensitivity. Riluzole thus has a marked inhibitory effect on HM activity by membrane hyperpolarization, decreasing firing and inhibiting glutamatergic excitation by both pre- and postsynaptic mechanisms. These results broaden the range of mechanisms controlling motor neuron inhibition by riluzole and are relevant to researchers and clinicians interested in understanding ALS pathogenesis and treatment.
Keyword Persistent sodium current
Excitatory synaptic transmission
Hyperpolarization-activated cation current
Ionotropic glutamate receptor
Amyotrophic lateral sclerosis
Motoneurons in-vitro
Neuroprotective agent riluzole
Neocortical pyramidal neurons
Paired-pulse facilitation
Respiratory rhythm
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Biomedical Sciences Publications
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