scholarly journals Hyperexcitability precedes motoneuron loss in the Smn2B/− mouse model of spinal muscular atrophy

2019 ◽  
Vol 122 (4) ◽  
pp. 1297-1311 ◽  
Author(s):  
K. A. Quinlan ◽  
E. J. Reedich ◽  
W. D. Arnold ◽  
A. C. Puritz ◽  
C. F. Cavarsan ◽  
...  
Keyword(s):  
Cell Death ◽  
Mouse Model ◽  
Action Potential ◽  
Spinal Muscular Atrophy ◽  
Postnatal Development ◽  
Motor Unit ◽  
Muscular Atrophy ◽  
Action Potential Firing ◽  
Motor Unit Number Estimation ◽  
Potential Firing

Spinal motoneuron dysfunction and loss are pathological hallmarks of the neuromuscular disease spinal muscular atrophy (SMA). Changes in motoneuron physiological function precede cell death, but how these alterations vary with disease severity and motoneuron maturational state is unknown. To address this question, we assessed the electrophysiology and morphology of spinal motoneurons of presymptomatic Smn2B/− mice older than 1 wk of age and tracked the timing of motor unit loss in this model using motor unit number estimation (MUNE). In contrast to other commonly used SMA mouse models, Smn2B/− mice exhibit more typical postnatal development until postnatal day (P)11 or 12 and have longer survival (~3 wk of age). We demonstrate that Smn2B/− motoneuron hyperexcitability, marked by hyperpolarization of the threshold voltage for action potential firing, was present at P9–10 and preceded the loss of motor units. Using MUNE studies, we determined that motor unit loss in this mouse model occurred 2 wk after birth. Smn2B/− motoneurons were also larger in size, which may reflect compensatory changes taking place during postnatal development. This work suggests that motoneuron hyperexcitability, marked by a reduced threshold for action potential firing, is a pathological change preceding motoneuron loss that is common to multiple models of severe SMA with different motoneuron maturational states. Our results indicate voltage-gated sodium channel activity may be altered in the disease process. NEW & NOTEWORTHY Changes in spinal motoneuron physiologic function precede cell death in spinal muscular atrophy (SMA), but how they vary with maturational state and disease severity remains unknown. This study characterized motoneuron and neuromuscular electrophysiology from the Smn2B/− model of SMA. Motoneurons were hyperexcitable at postnatal day (P)9–10, and specific electrophysiological changes in Smn2B/− motoneurons preceded functional motor unit loss at P14, as determined by motor unit number estimation studies.

scholarly journals Nicotine suppresses hyperexcitability of colonic sensory neurons and visceral hypersensivity in mouse model of colonic inflammation

2012 ◽  
Vol 302 (7) ◽  
pp. G740-G747 ◽  
Author(s):  
Galya R. Abdrakhmanova ◽  
Minho Kang ◽  
M. Imad Damaj ◽  
Hamid I. Akbarali
Keyword(s):  
Mouse Model ◽  
Action Potential ◽  
Action Potentials ◽  
Drg Neurons ◽  
Action Potential Firing ◽  
Colonic Inflammation ◽  
Single Action ◽  
Nicotine Administration ◽  
Potential Firing

Recently, we reported that nicotine in vitro at a low 1-μM concentration suppresses hyperexcitability of colonic dorsal root ganglia (DRG; L1-L2) neurons in the dextran sodium sulfate (DSS)-induced mouse model of acute colonic inflammation ( 1 ). Here we show that multiple action potential firing in colonic DRG neurons persisted at least for 3 wk post-DSS administration while the inflammatory signs were diminished. Similar to that in DSS-induced acute colitis, bath-applied nicotine (1 μM) gradually reduced regenerative multiple-spike action potentials in colonic DRG neurons to a single action potential in 3 wk post-DSS neurons. Nicotine (1 μM) shifted the activation curve for tetrodotoxin (TTX)-resistant sodium currents in inflamed colonic DRG neurons (voltage of half-activation changed from −37 to −32 mV) but did not affect TTX-sensitive currents in control colonic DRG neurons. Further, subcutaneous nicotine administration (2 mg/kg b.i.d.) in DSS-treated C57Bl/J6 male mice resulted in suppression of hyperexcitability of colonic DRG (L1-L2) neurons and the number of abdominal constrictions in response to intraperitoneal injection of 0.6% acetic acid. Collectively, the data suggest that neuronal nicotinic acetylcholine receptor-mediated suppression of hyperexcitability of colonic DRG neurons attenuates reduction of visceral hypersensitivity in DSS mouse model of colonic inflammation.

scholarly journals Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen

2020 ◽  
Vol 92 (1) ◽  
pp. 78-85 ◽  
Author(s):  
Didu Kariyawasam ◽  
Arlene D'Silva ◽  
James Howells ◽  
Karen Herbert ◽  
Peter Geelan-Small ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Unit ◽  
Therapeutic Response ◽  
Muscular Atrophy ◽  
Compound Muscle Action Potential ◽  
Motor Unit Potential ◽  
Abductor Pollicis Brevis ◽  
Electrophysiological Response ◽  
Single Motor Unit ◽  
Motor Unit Number Estimation

ObjectivesTo elucidate the motor unit response to intrathecal nusinersen in children with symptomatic spinal muscular atrophy (SMA) using a novel motor unit number estimation technique.MethodsMScanFit MUNE studies were sequentially undertaken from the abductor pollicis brevis muscle after stimulation of the median nerve in a prospective cohort of symptomatic children with SMA, undergoing intrathecal treatment with nusinersen at a single neuromuscular centre from June 2017 to August 2019. Electrophysiological measures included compound muscle action potential (CMAP), motor unit number estimation (MUNE), motor unit number contributing to 50%–100% of CMAP (N50) and measures of collateral reinnervation including largest single motor unit potential (LSMUP) and amplitude of the smallest unit contributing to N50 (A50).ResultsTwenty children (median age 99 months, range 4–193) were followed for a median of 13.8 (4–33.5) months. Therapeutic intervention was an independent and significant contributor to an increase in CMAP (p = 0.005), MUNE (p = 0.001) and N50 (p = 0.04). The magnitude of this electrophysiological response was increased in children with shorter disease durations (p<0.05). Electrophysiological changes delineated children who were functionally stable from those who attained clinically significant gains in motor function.InterpretationNusinersen therapy facilitated functional innervation in SMA through recovery of smaller motor units. Delineation of biomechanisms of therapeutic response may be the first step in identifying potential novel targets for disease modification in this and other motor neuropathies. MScanFit MUNE techniques may have a broader role in establishing biomarkers of therapeutic response in similar adult-onset diseases.

scholarly journals Persistent and resurgent Na+ currents in vestibular calyx afferents

2020 ◽  
Vol 124 (2) ◽  
pp. 510-524
Author(s):  
Frances L. Meredith ◽  
Katherine J. Rennie
Keyword(s):  
Action Potential ◽  
Postnatal Development ◽  
Afferent Neurons ◽  
Biophysical Properties ◽  
Action Potential Firing ◽  
Firing Patterns ◽  
Na Currents ◽  
Potential Firing ◽  
New Treatments ◽  
Afferent Terminals

Action potential firing patterns differ between groups of afferent neurons innervating vestibular epithelia. We investigated the biophysical properties of Na+ currents in specialized vestibular calyx afferent terminals during postnatal development. Mature calyces express Na+ currents with transient, persistent, and resurgent components. Nav1.6 channels contribute to resurgent Na+ currents and may enhance firing in peripheral calyx afferents. Understanding Na+ channels that contribute to vestibular nerve responses has implications for developing new treatments for vestibular dysfunction.

P915: Longitudinal motor unit number estimation in a spinal muscular atrophy cohort

2014 ◽  
Vol 125 ◽  
pp. S198
Author(s):  
P. Kaufmann ◽  
◽  
P.B. Kang ◽  
C.L. Gooch ◽  
M.P. McDermott ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Unit ◽  
Muscular Atrophy ◽  
Motor Unit Number Estimation

scholarly journals Optogenetically Controlled Activity Pattern Determines Survival Rate of Developing Neocortical Neurons

2021 ◽  
Vol 22 (12) ◽  
pp. 6575
Author(s):  
I. Emeline Wong Fong Sang ◽  
Jonas Schroer ◽  
Lisa Halbhuber ◽  
Davide Warm ◽  
Jenq-Wei Yang ◽  
...  
Keyword(s):  
Cell Death ◽  
Action Potential ◽  
Cortical Neurons ◽  
Firing Pattern ◽  
Neuronal Survival ◽  
Temporal Structure ◽  
Burst Stimulation ◽  
Action Potential Firing ◽  
Death Rates ◽  
Potential Firing

A substantial proportion of neurons undergoes programmed cell death (apoptosis) during early development. This process is attenuated by increased levels of neuronal activity and enhanced by suppression of activity. To uncover whether the mere level of activity or also the temporal structure of electrical activity affects neuronal death rates, we optogenetically controlled spontaneous activity of synaptically-isolated neurons in developing cortical cultures. Our results demonstrate that action potential firing of primary cortical neurons promotes neuronal survival throughout development. Chronic patterned optogenetic stimulation allowed to effectively modulate the firing pattern of single neurons in the absence of synaptic inputs while maintaining stable overall activity levels. Replacing the burst firing pattern with a non-physiological, single pulse pattern significantly increased cell death rates as compared to physiological burst stimulation. Furthermore, physiological burst stimulation led to an elevated peak in intracellular calcium and an increase in the expression level of classical activity-dependent targets but also decreased Bax/BCL-2 expression ratio and reduced caspase 3/7 activity. In summary, these results demonstrate at the single-cell level that the temporal pattern of action potentials is critical for neuronal survival versus cell death fate during cortical development, besides the pro-survival effect of action potential firing per se.

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