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  • 1
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    Online Resource
    Central Suppression of Regenerated Proprioceptive Afferents
    Society for Neuroscience ; 2005
    In:  The Journal of Neuroscience Vol. 25, No. 19 ( 2005-05-11), p. 4733-4742
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 25, No. 19 ( 2005-05-11), p. 4733-4742
    Abstract: Long after a cut peripheral nerve reinnervates muscle and restores force production in adult cats, the muscle does not respond reflexively to stretch. Motivated by the likelihood that stretch areflexia is related to problems with sensing and controlling limb position after peripheral neuropathies, we sought to determine the underlying mechanism. Electrophysiological and morphological measurements were made in anesthetized rats having one of the nerves to the triceps surae muscles either untreated or cut and immediately rejoined surgically many months earlier. First, it was established that reinnervated muscles failed to generate stretch reflexes, extending observations of areflexia to a second species. Next, multiple elements in the sensorimotor circuit of the stretch reflex were examined in both the PNS and CNS. Encoding of muscle stretch by regenerated proprioceptive afferents was remarkably similar to normal, although we observed some expected abnormalities, e.g., increased length threshold. However, the robust stretch-evoked sensory response that arrived concurrently at the CNS in multiple proprioceptive afferents produced synaptic responses that were either smaller than normal or undetectable. Muscle stretch failed to evoke detectable synaptic responses in 13 of 22 motoneurons, although electrical stimulation generated monosynaptic excitatory postsynaptic potentials that were indistinguishable from normal. The ineffectiveness of muscle stretch was not attributable therefore to dysfunction at synapses made between regenerated Ia afferents and motoneurons. Among multiple candidate mechanisms, we suggest that centrally controlled neural circuits may actively suppress the sensory information encoded by regenerated proprioceptive afferents to prevent recovery of the stretch reflex.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.4895-04.2005
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2005
    detail.hit.zdb_id: 1475274-8
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  • 2
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    Online Resource
    Prolongation of Evoked and Spontaneous Synaptic Currents at the Neuromuscular Junction after Activity Blockade Is Caused by the Upregulation of Fetal Acetylcholine Receptors
    Society for Neuroscience ; 2006
    In:  The Journal of Neuroscience Vol. 26, No. 35 ( 2006-08-30), p. 8983-8987
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 26, No. 35 ( 2006-08-30), p. 8983-8987
    Abstract: It has been shown previously in a number of systems that after an extended block of activity, synaptic strength is increased. We found that an extended block of synaptic activity at the mouse neuromuscular junction, using a tetrodotoxin cuff in vivo , increased synaptic strength by prolonging the evoked endplate current (EPC) decay. Prolongation of EPC decay was accompanied by only modest prolongation of spontaneous miniature EPC (MEPC) decay. Prolongation of EPC decay was reversed when quantal content was lowered by reducing extracellular calcium. These findings suggested that the cause of EPC prolongation was presynaptic in origin. However, when we acutely inhibited fetal-type acetylcholine receptors (AChRs) using a novel peptide toxin (αA-conotoxin OIVA[K15N]), prolongation of both EPC and MEPC decay were reversed. We also blocked synaptic activity in a mutant strain of mice in which persistent muscle activity prevents upregulation of fetal-type AChRs. In these mice, there was no prolongation of EPC decay. We conclude that upregulation of fetal-type AChRs after blocking synaptic activity causes modest prolongation of MEPC decay that is accompanied by much greater prolongation of EPC decay. This might occur if acetylcholine escapes from endplates and binds to extrajunctional fetal-type AChRs only during large, evoked EPCs. Our study is the first to demonstrate a functional role for upregulation of extrajunctional AChRs.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.2493-06.2006
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2006
    detail.hit.zdb_id: 1475274-8
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  • 3
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    Online Resource
    Synaptic Deficits at Neuromuscular Junctions in Two Mouse Models of Charcot–Marie–Tooth Type 2d
    Society for Neuroscience ; 2016
    In:  The Journal of Neuroscience Vol. 36, No. 11 ( 2016-03-16), p. 3254-3267
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 36, No. 11 ( 2016-03-16), p. 3254-3267
    Abstract: Patients with Charcot–Marie–Tooth Type 2D (CMT2D), caused by dominant mutations in Glycl tRNA synthetase ( GARS ), present with progressive weakness, consistently in the hands, but often in the feet also. Electromyography shows denervation, and patients often report that early symptoms include cramps brought on by cold or exertion. Based on reported clinical observations, and studies of mouse models of CMT2D, we sought to determine whether weakened synaptic transmission at the neuromuscular junction (NMJ) is an aspect of CMT2D. Quantal analysis of NMJs in two different mouse models of CMT2D ( Gars P278KY , Gars C201R ), found synaptic deficits that correlated with disease severity and progressed with age. Results of voltage-clamp studies revealed presynaptic defects characterized by: (1) decreased frequency of spontaneous release without any change in quantal amplitude (miniature endplate current), (2) reduced amplitude of evoked release (endplate current) and quantal content, (3) age-dependent changes in the extent of depression in response to repetitive stimulation, and (4) release failures at some NMJs with high-frequency, long-duration stimulation. Drugs that modify synaptic efficacy were tested to see whether neuromuscular performance improved. The presynaptic action of 3,4 diaminopyridine was not beneficial, whereas postsynaptic-acting physostigmine did improve performance. Smaller mutant NMJs with correspondingly fewer vesicles and partial denervation that eliminates some release sites also contribute to the reduction of release at a proportion of mutant NMJs. Together, these voltage-clamp data suggest that a number of release processes, while essentially intact, likely operate suboptimally at most NMJs of CMT2D mice. SIGNIFICANCE STATEMENT We have uncovered a previously unrecognized aspect of axonal Charcot–Marie–Tooth disease in mouse models of CMT2D. Synaptic dysfunction contributes to impaired neuromuscular performance and disease progression. This suggests that drugs which improve synaptic efficacy at the NMJ could be considered in treating the pathophysiology of CMT2D patients.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1762-15.2016
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2016
    detail.hit.zdb_id: 1475274-8
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  • 4
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    Online Resource
    Motor unit behavior in canine motor neuron disease
    Society for Neuroscience ; 1995
    In:  The Journal of Neuroscience Vol. 15, No. 5 ( 1995-05-01), p. 3447-3457
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 15, No. 5 ( 1995-05-01), p. 3447-3457
    Abstract: Hereditary canine spinal muscular atrophy (HCSMA) is an autosomally dominant disease of motor neurons that shares many pathological features with human motor neuron disease. A particularly striking feature of the affected, accelerated phenotype (homozygous HCSMA) is that profound weakness develops before appreciable motor neuron cell death occurs (Cork et al., 1989a), implying that motor unit functional defects occur initially. The purpose of this study was to identify the site of these defects and characterize their nature. In most young homozygotes (2–3 months postnatal), motor neurons were encountered that could support orthodromic action potential propagation to the muscle but did not activate muscle fibers. The tetanic forces of innervated motor units in young homozygotes tended to be smaller than those in closely age-matched clinically normal animals. In older homozygotes (approximately 4.5 months, postnatal), all motor neurons sampled were capable of activating muscle fibers, but many motor units displayed abnormal behavior including an inability to sustain force output during high frequency activation. Motor units exhibiting tetanic failure also showed proportionately greater twitch potentiation than nonfailing units of similar unpotentiated twitch amplitude. Tetanic failure and large potentiation tended to occur in motor units that possessed the slowest contraction speeds. These results indicate that motor neuron functional defects in HCSMA appear initially in the most distal parts of the motor axon and involve defective neurotransmission. The possible roles of distal nerve degeneration, motor terminal sprouting, and synaptic transmission in causing these deficits are considered.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.15-05-03447.1995
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 1995
    detail.hit.zdb_id: 1475274-8
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  • 5
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    Nerve Injury Induces Gap Junctional Coupling among Axotomized Adult Motor Neurons
    Society for Neuroscience ; 2000
    In:  The Journal of Neuroscience Vol. 20, No. 2 ( 2000-01-15), p. 674-684
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 20, No. 2 ( 2000-01-15), p. 674-684
    Abstract: Neonatal spinal motor neurons are electrically and dye-coupled by gap junctions, but coupling is transient and disappears rapidly after birth. Here we report that adult motor neurons become recoupled by gap junctions after peripheral nerve injury. One and 4–6 weeks after nerve cut, clusters of dye-coupled motor neurons were observed among axotomized, but not control, lumbar spinal motor neurons in adult cats. Electrical coupling was not apparent, probably because of the electrotonic distance between dendrodendritic gap junctions and the somatic recording location. Analyses of gap junction protein expression in cat and rat showed that the repertoire of connexins expressed by normal adult motor neurons, Cx36, Cx37, Cx40, Cx43, and Cx45, was unchanged after axotomy. Our results suggest that the reestablishment of gap junctional coupling among axotomized adult motor neurons may occur by modulation of existing gap junction proteins that are constitutively expressed by motor neurons. After injury, interneuronal gap junctional coupling may mediate signaling that maintains the viability of axotomized motor neurons until synaptic connections are reestablished within their targets.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.20-02-00674.2000
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2000
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 6
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    Online Resource
    Retrograde Mitochondrial Transport Is Essential for Organelle Distribution and Health in Zebrafish Neurons
    Society for Neuroscience ; 2021
    In:  The Journal of Neuroscience Vol. 41, No. 7 ( 2021-02-17), p. 1371-1392
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 41, No. 7 ( 2021-02-17), p. 1371-1392
    Abstract: In neurons, mitochondria are transported by molecular motors throughout the cell to form and maintain functional neural connections. These organelles have many critical functions in neurons and are of high interest as their dysfunction is associated with disease. While the mechanics and impact of anterograde mitochondrial movement toward axon terminals are beginning to be understood, the frequency and function of retrograde (cell body directed) mitochondrial transport in neurons are still largely unexplored. While existing evidence indicates that some mitochondria are retrogradely transported for degradation in the cell body, the precise impact of disrupting retrograde transport on the organelles and the axon was unknown. Using long-term, in vivo imaging, we examined mitochondrial motility in zebrafish sensory and motor axons. We show that retrograde transport of mitochondria from axon terminals allows replacement of the axon terminal population within a day. By tracking these organelles, we show that not all mitochondria that leave the axon terminal are degraded; rather, they persist over several days. Disrupting retrograde mitochondrial flux in neurons leads to accumulation of aged organelles in axon terminals and loss of cell body mitochondria. Assays of neural circuit activity demonstrated that disrupting mitochondrial transport and function has no effect on sensory axon terminal activity but does negatively impact motor neuron axons. Taken together, our work supports a previously unappreciated role for retrograde mitochondrial transport in the maintenance of a homeostatic distribution of mitochondria in neurons and illustrates the downstream effects of disrupting this process on sensory and motor circuits. SIGNIFICANCE STATEMENT Disrupted mitochondrial transport has been linked to neurodegenerative disease. Retrograde transport of this organelle has been implicated in turnover of aged organelles through lysosomal degradation in the cell body. Consistent with this, we provide evidence that retrograde mitochondrial transport is important for removing aged organelles from axons; however, we show that these organelles are not solely degraded, rather they persist in neurons for days. Disrupting retrograde mitochondrial transport impacts the homeostatic distribution of mitochondria throughout the neuron and the function of motor, but not sensory, axon synapses. Together, our work shows the conserved reliance on retrograde mitochondrial transport for maintaining a healthy mitochondrial pool in neurons and illustrates the disparate effects of disrupting this process on sensory versus motor circuits.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1316-20.2020
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2021
    detail.hit.zdb_id: 1475274-8
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  • 7
    Online Resource
    Online Resource
    Effects of 4-Aminopyridine on Muscle and Motor Unit Force in Canine Motor Neuron Disease
    Society for Neuroscience ; 1997
    In:  The Journal of Neuroscience Vol. 17, No. 11 ( 1997-06-01), p. 4500-4507
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 17, No. 11 ( 1997-06-01), p. 4500-4507
    Abstract: Hereditary Canine Spinal Muscular Atrophy (HCSMA) is an autosomal dominant disorder of motor neurons that shares features with human motor neuron disease. In animals exhibiting the accelerated phenotype (homozygotes), we demonstrated previously that many motor units exhibit functional deficits that likely reflect underlying deficits in neurotrans-mission. The drug 4-aminopyridine (4AP) blocks voltage-dependent potassium conductances and is capable of increasing neurotransmission by overcoming axonal conduction block or by increasing transmitter release. In this study, we determined whether and to what extent 4AP could enhance muscle force production in HCSMA. Systemic 4AP (1–2 mg/kg) increased nerve-evoked whole muscle twitch force and electromyograms (EMG) to a greater extent in older homozygous animals than in similarly aged, symptomless HCSMA animals or in one younger homozygous animal. The possibility that this difference was caused by the presence of failing motor units in the muscles from homozygotes was tested directly by administering 4AP while recording force produced by failing motor units. The results showed that the twitch force and EMG of failing motor units could be significantly increased by 4AP, whereas no effect was observed in a nonfailing motor unit from a symptomless, aged-matched HCSMA animal. The ability of 4AP to increase force in failing units may be related to the extent of failure. Although 4AP increased peak forces during unit tetanic activation, tetanic force failure was not eliminated. These results demonstrate that the force outputs of failing motor units in HCSMA homozygotes can be increased by 4AP. Possible sites of 4AP action are considered.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.17-11-04500.1997
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 1997
    detail.hit.zdb_id: 1475274-8
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  • 8
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    Online Resource
    Trimetazidine Use in Parkinson’s Disease: Is It a Resolved Problem?
    Society for Neuroscience ; 2021
    In:  eneuro Vol. 8, No. 3 ( 2021-05), p. ENEURO.0452-20.2021-
    Details
    In: eneuro, Society for Neuroscience, Vol. 8, No. 3 ( 2021-05), p. ENEURO.0452-20.2021-
    Abstract: Trimetazidine (TMZ), an antianginal drug, can worsen the symptoms of movement disorders, therefore, the European Medicines Agency (EMA) recommended avoiding the use of this drug in Parkinson’s disease (PD). We investigated the impact of this recommendation on the observed trend of TMZ use in PD in Hungary from 2010 to 2016 by conducting a nationwide, retrospective study of health administrative data of human subjects. Interrupted time series analyses were performed to explore changes in user trends after the EMA recommendations. We found that TMZ use in PD decreased by 6.56% in each six-month interval after the EMA intervention [a change in trend of −530.22, 95% confidence interval (CI) = −645.00 to −415.44, p 〈 0.001 and a decrease in level of −567.26, 95% CI = −910.99 to −223.53, p  = 0.005 12 months postintervention]. TMZ discontinuation was the highest immediately after the intervention, however, its rate slowed down subsequently (a change in trend of −49.69, 95% CI = −85.14 to −14.24, p  = 0.11 without significant level effects). The rate of new TMZ prescriptions did not reduce significantly, therefore, the decreased overall use was mainly attributable to the increased rate of discontinuation only. The main indications for TMZ use were circulatory system disorders, especially angina pectoris, however, off-label utilization was also considerable (40%). The EMA recommendations on TMZ use seem to be only moderately effective in Hungary. Although the number of patients with PD on the drug modestly decreased after the EMA restrictions, TMZ is still widely used in PD for both on-label and off-label indications.
    Type of Medium: Online Resource
    ISSN: 2373-2822
    URL: Article
    DOI: 10.1523/ENEURO.0452-20.2021
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2021
    detail.hit.zdb_id: 2800598-3
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  • 9
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    Online Resource
    Transient Receptor Potential Channel Ankyrin-1 Is Not a Cold Sensor for Autonomic Thermoregulation in Rodents
    Society for Neuroscience ; 2014
    In:  The Journal of Neuroscience Vol. 34, No. 13 ( 2014-03-26), p. 4445-4452
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 34, No. 13 ( 2014-03-26), p. 4445-4452
    Abstract: The rodent transient receptor potential ankyrin-1 (TRPA1) channel has been hypothesized to serve as a temperature sensor for thermoregulation in the cold. We tested this hypothesis by using deletion of the Trpa1 gene in mice and pharmacological blockade of the TRPA1 channel in rats. In both Trpa1 −/− and Trpa1 +/+ mice, severe cold exposure (8°C) resulted in decreases of skin and deep body temperatures to ∼8°C and 13°C, respectively, both temperatures being below the reported 17°C threshold temperature for TRPA1 activation. Under these conditions, Trpa1 −/− mice had the same dynamics of body temperature as Trpa1 +/+ mice and showed no weakness in the tail skin vasoconstriction response or thermogenic response to cold. In rats, the effects of pharmacological blockade were studied by using two chemically unrelated TRPA1 antagonists: the highly potent and selective compound A967079, which had been characterized earlier, and the relatively new compound 43 ((4 R )-1,2,3,4-tetrahydro-4-[3-(3-methoxypropoxy)phenyl]-2-thioxo-5 H -indeno[1,2- d ]pyrimidin-5-one), which we further characterized in the present study and found to be highly potent (IC 50 against cold of ∼8 n m ) and selective. Intragastric administration of either antagonist at 30 mg/kg before severe (3°C) cold exposure did not affect the thermoregulatory responses (deep body and tail skin temperatures) of rats, even though plasma concentrations of both antagonists well exceeded their IC 50 value at the end of the experiment. In the same experimental setup, blocking the melastatin-8 (TRPM8) channel with AMG2850 (30 mg/kg) attenuated cold-defense mechanisms and led to hypothermia. We conclude that TRPA1 channels do not drive autonomic thermoregulatory responses to cold in rodents.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.5387-13.2014
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2014
    detail.hit.zdb_id: 1475274-8
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  • 10
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    Online Resource
    Reversible Recruitment of a Homeostatic Reserve Pool of Synaptic Vesicles Underlies Rapid Homeostatic Plasticity of Quantal Content
    Society for Neuroscience ; 2016
    In:  The Journal of Neuroscience Vol. 36, No. 3 ( 2016-01-20), p. 828-836
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 36, No. 3 ( 2016-01-20), p. 828-836
    Abstract: Homeostatic regulation is essential for the maintenance of synaptic strength within the physiological range. The current study is the first to demonstrate that both induction and reversal of homeostatic upregulation of synaptic vesicle release can occur within seconds of blocking or unblocking acetylcholine receptors at the mouse neuromuscular junction. Our data suggest that the homeostatic upregulation of release is due to Ca 2+ -dependent increase in the size of the readily releasable pool (RRP). Blocking vesicle refilling prevented upregulation of quantal content (QC), while leaving baseline release relatively unaffected. This suggested that the upregulation of QC was due to mobilization of a distinct pool of vesicles that were rapidly recycled and thus were dependent on continued vesicle refilling. We term this pool the “homeostatic reserve pool.” A detailed analysis of the time course of vesicle release triggered by a presynaptic action potential suggests that the homeostatic reserve pool of vesicles is normally released more slowly than other vesicles, but the rate of their release becomes similar to that of the major pool during homeostatic upregulation of QC. Remarkably, instead of finding a generalized increase in the recruitment of vesicles into RRP, we identified a distinct homeostatic reserve pool of vesicles that appear to only participate in synchronized release following homeostatic upregulation of QC. Once this small pool of vesicles is depleted by the block of vesicle refilling, homeostatic upregulation of QC is no longer observed. This is the first identification of the population of vesicles responsible for the blockade-induced upregulation of release previously described. SIGNIFICANCE STATEMENT The current study is the first to demonstrate that both the induction and reversal of homeostatic upregulation of synaptic vesicle release can occur within seconds. Our data suggest that homeostatic upregulation of release is due to Ca 2+ -dependent priming/docking of a small homeostatic reserve pool of vesicles that normally have slow-release kinetics. Following priming, the reserve pool of vesicles is released synchronously with the normal readily releasable pool of synaptic vesicles. This is the first description of this unique pool of synaptic vesicles.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.3786-15.2016
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2016
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    SSG: 12
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