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1.
Mol Cell Neurosci ; 125: 103840, 2023 06.
Article in English | MEDLINE | ID: mdl-36921783

ABSTRACT

An altered neuronal excitability of spinal motoneurones has consistently been implicated in Amyotrophic Lateral Sclerosis (ALS) leading to several investigations of synaptic input to these motoneurones. One such input that has repeatedly been shown to be affected is a population of large cholinergic synapses terminating mainly on the soma of the motoneurones referred to as C-boutons. Most research on these synapses during disease progression has used transgenic Superoxide Dismutase 1 (SOD1) mouse models of the disease which have not only produced conflicting findings, but also fail to recapitulate the key pathological feature seen in ALS; cytoplasmic accumulations of TAR DNA-binding protein 43 (TDP-43). Additionally, they fail to distinguish between slow and fast motoneurones, the latter of which have more C-boutons, but are lost earlier in the disease. To circumvent these issues, we quantified the frequency and volume of C-boutons on traced soleus and gastrocnemius motoneurones, representing predominantly slow and fast motor pools respectively. Experiments were performed using the TDP-43ΔNLS mouse model that carries a transgenic construct of TDP-43 devoid of its nuclear localization signal, preventing its nuclear import. This results in the emergence of pathological TDP-43 inclusions in the cytoplasm, modelling the main pathology seen in this disorder, accompanied by a severe and lethal ALS phenotype. Our results confirmed changes in both the number and volume of C-boutons with a decrease in number on the more vulnerable, predominantly fast gastrocnemius motoneurones and an increase in number on the less vulnerable, predominantly slow soleus motoneurones. Importantly, these changes were only found in male mice. However, both sexes and motor pools showed a decrease in C-bouton volume. Our experiments confirm that cytoplasmic TDP-43 accumulation is sufficient to drive C-bouton changes.


Subject(s)
Amyotrophic Lateral Sclerosis , Female , Male , Mice , Animals , Amyotrophic Lateral Sclerosis/metabolism , Spinal Cord/metabolism , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism , Motor Neurons/metabolism , Mice, Transgenic , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Disease Models, Animal
2.
Exp Neurol ; 331: 113361, 2020 09.
Article in English | MEDLINE | ID: mdl-32464119

ABSTRACT

The morphology and projections of ventral horn interneurones in the segment above an ipsilateral thoracic lateral spinal cord lesion were studied in the cat by intracellular injections of Neurobiotin at 6 to 18 weeks post-lesion and compared with previously published control data from uninjured spinal cords. The cell axons ascended, descended or both, mostly contralaterally and mostly spared by the lesion. Unusual morphological dendritic features were seen in the lesion group, mostly growth-related, including complex dendritic appendages, twisted or multiple-branched terminal dendrites, commissural dendrites, apparently swollen proximal dendrites and rostrocaudal asymmetries. Significant quantitative differences included more dendritic spines in the lesion group (3.4×) and smaller soma areas in the lesion group (with similar numbers of primary dendrites and rostrocaudal dendritic spans). Immunoreactivity to microtubule associated protein 2a/b was detected in the proximal, but not distal, dendrites of cells in the lesion group, corresponding to an overall decrease in immunoreactivity in the ventral horns on the lesion side compared to the other. For axon collaterals, significant increases for the lesion group were seen in the number of collaterals in the first 4 mm of axon and in the area of ventral/intermediate horn occupied by terminals, including increased innervation of some regions, among which were the intermediolateral columns. This dendritic and axonal plasticity makes the interneuones candidates for a role in detour circuits but also for a maladaptive role in autonomic hyperreflexia.


Subject(s)
Interneurons/physiology , Neuronal Plasticity/physiology , Spinal Cord Injuries/physiopathology , Animals , Cats , Female , Male , Thoracic Vertebrae
3.
J Neurosci ; 38(45): 9741-9753, 2018 11 07.
Article in English | MEDLINE | ID: mdl-30249797

ABSTRACT

In the motor system, force gradation is achieved by recruitment of motoneurons and rate modulation of their firing frequency. Classical experiments investigating the relationship between injected current to the soma during intracellular recording and the firing frequency (the I-f relation) in cat spinal motoneurons identified two clear ranges: a primary range and a secondary range. Recent work in mice, however, has identified an additional range proposed to be exclusive to rodents, the subprimary range (SPR), due to the presence of mixed mode oscillations of the membrane potential. Surprisingly, fully summated tetanic contractions occurred in mice during SPR frequencies. With the mouse now one of the most popular models to investigate motor control, it is crucial that such discrepancies between observations in mice and basic principles that have been widely accepted in larger animals are resolved. To do this, we have reinvestigated the I-f relation using ramp current injections in spinal motoneurons in both barbiturate-anesthetized and decerebrate (nonanesthetized) cats and mice. We demonstrate the presence of the SPR and mixed mode oscillations in both species and show that the SPR is enhanced by barbiturate anesthetics. Our measurements of the I-f relation in both cats and mice support the classical opinion that firing frequencies in the higher end of the primary range are necessary to obtain a full summation. By systematically varying the leg oil pool temperature (from 37°C to room temperature), we found that only at lower temperatures can maximal summation occur at SPR frequencies due to prolongation of individual muscle twitches.SIGNIFICANCE STATEMENT This work investigates recent revelations that mouse motoneurons behave in a fundamentally different way from motoneurons of larger animals with respect to the importance of rate modulation of motoneuron firing for force gradation. The current study systematically addresses the proposed discrepancies between mice and larger species (cats) and demonstrates that mouse motoneurons, in fact, use rate modulation as a mechanism of force modulation in a similar manner to the classical descriptions in larger animals.


Subject(s)
Motor Neurons/physiology , Muscle Contraction/physiology , Muscle, Skeletal/physiology , Spinal Cord/physiology , Animals , Cats , Electric Stimulation/methods , Female , Male , Mice , Mice, Inbred C57BL , Muscle, Skeletal/innervation , Species Specificity , Spinal Cord/cytology
4.
Exp Neurol ; 292: 154-167, 2017 06.
Article in English | MEDLINE | ID: mdl-28322742

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease, which selectively affects upper and lower motoneurones. The underlying pathophysiology of the disease is complex but electrophysiological studies of peripheral nerves in ALS patients as well as human autopsy studies indicate that a potassium channel dysfunction/loss is present early in the symptomatic phase. It remains unclear to what extent potassium channel abnormalities reflect a specific pathogenic mechanism in ALS. The aim of this study was therefore to investigate the temporal changes in the expression and/or function of potassium channels in motoneurones in the adult G127X SOD1 mouse model of ALS, a model which has a very long presymptomatic phase. Evidence from animal models indicates that the early progressive motoneurone dysfunction and degeneration can be largely compensated by motor unit remodeling, delaying the clinical symptom onset. Experiments were therefore performed both before and after symptom onset. Immunohistochemistry of motor axons in the ventral roots of G127X SOD1 mice, was used to investigate juxta-paranodal Kv1.2 potassium channels along with nodal Nav1.6 and the paranodal scaffolding protein Caspr. This allowed an investigation of changes in the distribution of Kv1.2 relative to the general structure of the nodal-paranodal-juxta-paranodal complex. This revealed that the motor axons in the ventral roots of presymptomatic G127X SOD1 mice, already show a disruption in juxta-paranodal Kv1.2 potassium channels. The axonal Kv1.2 disruption was preceded by abnormalities in the distribution of the paranodal scaffolding protein Caspr with the nodal arrangement of Nav1.6 appearing relatively preserved even in symptomatic mice. These changes were accompanied by axon swelling and a slowing of conduction in the peripheral motor axons in symptomatic mice. In vivo electrophysiological intracellular recordings of individual spinal motoneurones revealed that central potassium channel function was preserved or even enhanced with higher amplitude and longer duration after-hyperpolarisations in the G127X SOD1 mice. Our data suggest that the potassium channel abnormalities observed in presymptomatic G127X, rather than representing a specific pathophysiological mechanism targeting potassium channels, most likely reflect early axonal degenerative changes, consistent with the "dying-back" phenomenon observed in other ALS models.


Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Axons/pathology , Motor Neurons/metabolism , Peripheral Nerves/metabolism , Potassium Channels/metabolism , Spinal Nerve Roots/metabolism , Amyotrophic Lateral Sclerosis/pathology , Animals , Axons/metabolism , Disease Models, Animal , Mice, Transgenic , Motor Neurons/pathology , Spinal Nerve Roots/pathology
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