Voltage-gated calcium channels are abnormal in cultured spinal motoneurons in the G93A-SOD1 transgenic mouse model of ALS

Chang, Qing; Martin, Lee J.

doi:10.1016/j.nbd.2016.04.009

Cited by 25 publications

(27 citation statements)

References 103 publications

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“…Additionally, the reduced expression of the astrocytic inwardly rectifying potassium channel 4.1 (Kir4.1) observed in hSOD1 G93A models may contribute to motor neuron degeneration and hyperexcitability through the impairment of potassium homeostasis [99, 100]. Lastly, abnormal voltage-gated calcium channel function has been reported in hSOD1 G93A cultured spinal motor neurons [101] and could be yet another mechanism influencing the sensitivity of motor neurons to excitotoxicity.…”

Section: Pathways Involved In Astrocyte-mediated Motor Neuron Toximentioning

confidence: 99%

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

Pehar

Harlan

Killoy

et al. 2018

CPD

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Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. The molecular mechanism underlying the progressive degeneration of motor neuron remains uncertain but involves a non-cell autonomous process. In acute injury or degenerative diseases astrocytes adopt a reactive phenotype known as astrogliosis. Astrogliosis is a complex remodeling of astrocyte biology and most likely represents a continuum of potential phenotypes that affect neuronal function and survival in an injury-specific manner. In ALS patients, reactive astrocytes surround both upper and lower degenerating motor neurons and play a key role in the pathology. It has become clear that astrocytes play a major role in ALS pathology. Through loss of normal function or acquired new characteristics, astrocytes are able to influence motor neuron fate and the progression of the disease. The use of different cell culture models indicates that ALS-astrocytes are able to induce motor neuron death by secreting a soluble factor(s). Here, we discuss several pathogenic mechanisms that have been proposed to explain astrocyte-mediated motor neuron death in ALS. In addition, examples of strategies that revert astrocyte-mediated motor neuron toxicity are reviewed to illustrate the therapeutic potential of astrocytes in ALS. Due to the central role played by astrocytes in ALS pathology, therapies aimed at modulating astrocyte biology may contribute to the development of integral therapeutic approaches to halt ALS progression.

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Section: Pathways Involved In Astrocyte-mediated Motor Neuron Toximentioning

confidence: 99%

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

Pehar

Harlan

Killoy

et al. 2018

CPD

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“…Whole-cell patch-clamp recordings. Whole-cell patch-clamp recordings were performed as described previously 27 . Nodose ganglia neurons from Vglut2-GCaMP3 mice were selected for recording by their Recording procedure and analysis.…”

Section: Proximity Ligation Assay (Pla): the Interactions Between Trpmentioning

confidence: 99%

Transient Receptor Potential Ankyrin 1 Mediates Afferent Signals in the Inflammatory Reflex

Silverman

Gunasekaran

Chang

et al. 2019

Preprint

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Survival of an organism requires mechanisms to sense damaging factors in the environment. In mammals, bacterial toxins and inflammatory mediators stimulate nociceptive sensory neurons to activate protective reflexes. Whereas the vagus nerve reflex circuit that protects against damaging inflammation, termed the "inflammatory reflex," was described more than twenty years ago 1,2 , how the vagus nerve detects inflammation to initiate the inflammatory reflex has remained unknown. Here we show that transient receptor potential ankyrin 1 (TRPA1) in sensory vagus neurons is required to sense interleukin-1β (IL-1β), a central cytokine mediator of inflammation and injury. Selective activation of vagus nerve TRPA1 using optopharmacology stimulated the inflammatory reflex to inhibit innate inflammatory responses to bacterial lipopolysaccharide and IL-1β. Proximity ligation assay and immunohistochemistry revealed that IL-1 receptors are coexpressed with TRPA1 in vagus sensory neurons. Whole-cell patch-clamp recordings reveal that TRPA1 is required to mediate IL-1β-dependent depolarization of vagus sensory neurons. Further, TRPA1-deficient mice lack inflammatory reflex attenuation of inflammation, fail to restrain cytokine release, and have significantly enhanced lethality to bacterial sepsis. Therefore, vagus neurons expressing TRPA1 are necessary and sufficient to activate the sensory arc of the inflammatory reflex to protect against harmful inflammation.Reflex neural circuits form the basis for physiological responses when the body is exposed to changing environmental and physiological conditions. The vagus nerve, originating in the brainstem medulla oblongata, is a paired structure that travels through the neck, thorax and abdomen to innervate visceral organs. In humans it is comprised of approximately 100,000 neurons; 80% are sensory, transmitting information to the brainstem in response to changes in the body's internal milieu to stimulate reflex motor signals that regulate heart rate, digestion, and other organ functions. The inflammatory reflex, a vagus circuit that inhibits inflammation to protect tissues from damage, stimulates anti-inflammatory T cells expressing choline acetyltransferase (T ChAT) in the spleen to produce acetylcholine which interacts with 7 nicotinic acetylcholine receptor (7nAChR)-expressing macrophages to inhibit release of TNF, IL-1, HMGB1 and other inflammatory cytokines 1-3 . Electronic stimulation of the inflammatory reflex confers significant protection in preclinical models of arthritis, inflammatory bowel disease, sepsis, and other syndromes, and significantly improves outcomes in clinical trials of rheumatoid arthritis and Crohn's disease 2,4,5 . Despite a detailed mechanistic understanding of signaling in the motor arc of the inflammatory reflex, the afferent arc mechanisms were previously unknown. TRPA1, a polymodal nociceptor cation channel expressed by unmyelinated peptidergic nociceptive C fiber neurons, is stimulated by reactive (hydrogen peroxide, formalin, acrolein) and non-rea...

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“…However, hyperexcitability was observed only in high-threshold α MNs (more susceptible to neurodegeneration) due to a downregulation of outward currents. Additionally, Chang and Martin (2016) reported an abnormal expression of voltage-gated Ca ++ channels, which results in an increase in Ca ++ currents and, consequently, α MN excitability. Conversely, other studies have provided evidence that intrinsic excitability of MNs are reduced during ALS development, both due to changes in MN morphology (Amendola and Durand, 2008) and electrophysiology (Delestrée et al, 2014).…”

Section: Motor Neuron Diseasementioning

confidence: 99%

Perspectives on the modeling of the neuromusculoskeletal system to investigate the influence of neurodegenerative diseases on sensorimotor control

et al. 2018

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The understanding of the neurophysiological mechanisms underlying movement control can be much furthered using computational models of the neuromusculoskeletal system. Biologically based multi-scale neuromusculoskeletal models have a great potential to provide new theories and explanations related to mechanisms behind muscle force generation at the molecular, cellular, synaptic, and systems levels. Albeit some efforts have been made to investigate how neurodegenerative diseases alter the dynamics of individual elements of the neuromuscular system, such diseases have not been analyzed from a systems viewpoint using multi-scale models. Overview and Perspectives: This perspective article synthesizes what has been done in terms of multi-scale neuromuscular development and points to a few directions where such models could be extended so that they can be useful in the future to discover early predictors of neurodegenerative diseases, as well as to propose new quantitative clinical neurophysiology approaches to follow the course of improvements associated with different therapies (drugs or others). Concluding Remarks: Therefore, this article will present how existing biologically based multi-scale models of the neuromusculoskeletal system could be expanded and adapted for clinical applications. It will point to mechanisms operating at different levels that would be relevant to be considered during model development, along with implications for interpreting experimental results from neurological patients.

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Voltage-gated calcium channels are abnormal in cultured spinal motoneurons in the G93A-SOD1 transgenic mouse model of ALS

Cited by 25 publications

References 103 publications

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

Transient Receptor Potential Ankyrin 1 Mediates Afferent Signals in the Inflammatory Reflex

Perspectives on the modeling of the neuromusculoskeletal system to investigate the influence of neurodegenerative diseases on sensorimotor control

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