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
Open Access Status DOI
Volume 110
Issue 5
Start page 1047
End page 1061
Total pages 15
Place of publication Bethesda, MD, United States
Publisher American Physiological Society
Language eng
Abstract Hypoglossal motor neurons (XII MNs) innervate tongue muscles important in breathing, suckling and vocalization. Morphological properties of 103 XII MNs were studied using Neurobiotin™ filling in transverse brainstem slices from C57/Bl6 mice (n = 34) from embryonic day (E) 17 to postnatal day (P) 28. XII MNs from areas thought to innervate different tongue muscles showed similar morphology in most, but not all, features. Morphological properties of XII MNs were established prior to birth, not differing between E17-18 and P0. MN somatic volume gradually increased for the first 2 weeks post-birth. The complexity of dendritic branching and dendrite length of XII MNs increased throughout development (E17-P28). MNs in the ventromedial XII motor nucleus, likely to innervate the genioglossus, frequently (42 %) had dendrites crossing to the contralateral side at all ages, but their number declined with postnatal development. Unexpectedly, putative dendritic spines were found in all XII MNs at all ages, and were primarily localized to XII MN somata and primary dendrites at E18-P4, increased in distal dendrites by P5-P8, and were later predominantly found in distal dendrites. Dye-coupling between XII MNs was common from E18 to P7, but declined strongly with maturation after P7. Axon collaterals were found in 20 % (6 of 28) of XII MNs with filled axons; collaterals terminated widely outside and, in one case, within the XII motor nucleus. These results reveal new morphological features of mouse XII MNs, and suggest that dendritic projection patterns, spine density and distribution, and dye-coupling patterns show specific developmental changes in mice.
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)
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