Localization and dynamic changes of neuregulin‐1 at C‐type synaptic boutons in association with motor neuron injury and repair

Salvany, Sara; Casanovas, Anna; Tarabal, Olga; Piedrafita, Lídia; Hernández, Sara; Santafé, Manuel M.; Soto-Bernardini, Maria Clara; Calderó, Jordi; Schwab, Markus H.; Esquerda, Josep E.

doi:10.1096/fj.201802329r

Cited by 27 publications

(46 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…VAChT is consolidated in literature to assess cholinergic innervation. This specific antibody was validated in several studies in the literature 31‐33 …”

Section: Methodsmentioning

confidence: 97%

Cholinergic neuroplasticity in asthma driven by TrkB signaling

et al. 2020

View full text Add to dashboard Cite

Parasympathetic neurons in the airways control bronchomotor tone. Increased activity of cholinergic neurons are mediators of airway hyperresponsiveness (AHR) in asthma, however, mechanisms are not elucidated. We describe remodeling of the cholinergic neuronal network in asthmatic airways driven by brain‐derived neurotrophic factor (BDNF) and Tropomyosin receptor kinase B (TrkB). Human bronchial biopsies were stained for cholinergic marker vesicular acetylcholine transporter (VAChT). Human lung gene expression and single nucleotide polymorphisms (SNP) in neuroplasticity‐related genes were compared between asthma and healthy patients. Wild‐type (WT) and mutated TrkB knock‐in mice (Ntrk2tm1Ddg/J) with impaired BDNF signaling were chronically exposed to ovalbumin (OVA). Neuronal VAChT staining and airway narrowing in response to electrical field stimulation in precision cut lung slices (PCLS) were assessed. Increased cholinergic fibers in asthmatic airway biopsies was found, paralleled by increased TrkB gene expression in human lung tissue, and SNPs in the NTRK2 [TrkB] and BDNF genes linked to asthma. Chronic allergen exposure in mice resulted in increased density of cholinergic nerves, which was prevented by inhibiting TrkB. Increased nerve density resulted in AHR in vivo and in increased nerve‐dependent airway reactivity in lung slices mediated via TrkB. These findings show cholinergic neuroplasticity in asthma driven by TrkB signaling and suggest that the BDNF‐TrkB pathway may be a potential target.

show abstract

“…VAChT is consolidated in literature to assess cholinergic innervation. This specific antibody was validated in several studies in the literature 31‐33 …”

Section: Methodsmentioning

confidence: 97%

Cholinergic neuroplasticity in asthma driven by TrkB signaling

et al. 2020

View full text Add to dashboard Cite

show abstract

“…A certain type of cholinergic synapse on spinal motoneurones; the C-bouton, plays a crucial role in the modulation of the motoneurone AHP of lumbar spinal neurones via their interaction with muscarinic (m2) receptors and the small conductance calcium-activated potassium (SK) channels mediating the AHP 17,18 . A reduction in the number and size of C-boutons on spinal motoneurones has been shown on axotomised motoneurones [19][20][21] which may explain the prolongation of the AHP observed after axotomy 22,23 . As BoNT/A injections induce similar (albeit less extreme) changes in the AHP 12 this suggests that a loss of functional connectivity at the neuromuscular junction may be enough to drive such changes in C-boutons.…”

mentioning

confidence: 93%

Intramuscular Botulinum toxin A injections induce central changes to axon initial segments and cholinergic boutons on spinal motoneurones in rats

Jensen

Klingenberg

Dimintiyanova

et al. 2020

Sci Rep

View full text Add to dashboard Cite

intramuscular injections of botulinum toxin block pre-synaptic cholinergic release at neuromuscular junctions producing a temporary paralysis of affected motor units. There is increasing evidence, however, that the effects are not restricted to the periphery and can alter the central excitability of the motoneurones at the spinal level. This includes increases in input resistance, decreases in rheobase currents for action potentials and prolongations of the post-spike after-hyperpolarization. the aim of our experiments was to investigate possible anatomical explanations for these changes. Unilateral injections of Botulinum toxin A mixed with a tracer were made into the gastrocnemius muscle of adult rats and contralateral tracer only injections provided controls. immunohistochemistry for Ankyrin G and the vesicular acetylcholine transporter labelled axon initial segments and cholinergic c-boutons on traced motoneurones at 2 weeks post-injection. Soma size was not affected by the toxin; however, axon initial segments were 5.1% longer and 13.6% further from the soma which could explain reductions in rheobase. Finally, there was a reduction in surface area (18.6%) and volume (12.8%) but not frequency of c-boutons on treated motoneurones potentially explaining prolongations of the afterhyperpolarization. Botulinum Toxin A therefore affects central anatomical structures controlling or modulating motoneurone excitability explaining previously observed excitability changes. Botulinum neurotoxin type-A (BoNT/A) is one of the most dangerous toxins known to man, yet it is being increasingly used, both cosmetically and clinically, to produce long lasting paralysis of specific muscles. After intramuscular injection, the toxin enters the synaptic vesicles of motor axon terminals by endocytosis. From here it silences synaptic transmission via specific proteolytic cleavage of SNAP-25 which prevents the release of acetylcholine from the motoneurone terminal resulting in flaccid paralysis 1. There is increasing evidence, however, that the effects may not be restricted to the periphery. Studies show that BoNT/A, injected intramuscularly, is transported both anterogradely along sensory axons and retrogradely along motoneurone axons to the motoneurone soma in the spinal cord 2-5. Furthermore, there is now also evidence that BoNT/A can spread between networks of cells 6 , although this claim has been questioned by other studies and would appear to be dose dependent 7,8. This raises the question as to what central effects BoNT/A may have on the motoneurone itself or on central cholinergic synapses contacting the motoneurone. Electrophysiological studies suggest changes in spinal motoneurone excitability after intramuscular BoNT/A injections of the gastrocnemius muscle. Increased stretch reflexes are seen at two weeks post-injection in rats 9. This increased reflex was also seen when tested as simple monosynaptic responses to dorsal root stimulation suggesting the enhanced reflexes may be due to an increase in motoneurone excitability 1...

show abstract

“…and phosphorylation and dimerization of these receptors leads to activation of downstream pathways (4). nrG-1 acts on multiple targets such as heart, blood vessels, nerves and interstitial fluid, and protects the myocardium, promoting the improvement of cardiac function through a combined multifaceted effect.…”

Section: Neuregulin-1: An Underlying Protective Force Of Cardiac Dysfmentioning

confidence: 99%

“…Sepsis-3 defines sepsis as a 'life-threatening organ dysfunction caused by abnormal reactions to infection', and recommends sequential organ failure assessment (SoFa) and quick SoFa scores as the basis for diagnosis of sepsis (5)(6)(7); however, it does not include the criteria for measuring target organ dysfunction (4)(5)(6)(7). Using this definition, 'host response' and 'organ dysfunction' are the two core elements considered to be involved in the complex pathophysiological reactions produced by the body in response to infection (4)(5)(6)(7). current understanding of the complex pathophysiological mechanisms involved in immune and inflammatory responses to sepsis remains incomplete, but it is clear that sepsis involves the immune system, accompanied by inflammation and microcirculatory failure.…”

Section: Presentation Of Sepsis-induced Cardiac Dysfunctionmentioning

confidence: 99%

Neuregulin‑1: An underlying protective force of cardiac dysfunction in sepsis (Review)

et al. 2020

View full text Add to dashboard Cite

neuregulin-1 (nrG-1) is a type of epidermal growth factor-like protein primarily distributed in the nervous and cardiovascular systems. When sepsis occurs, the incidence of cardiac dysfunction in myocardial injury is high and the mechanism is complicated. it directly causes myocardial cell damage, whilst also causing damage to the structure and function of myocardial cells, weakening of endothelial function and coronary microcirculation, autonomic dysfunction, and activation of myocardial inhibitory factors. Studies investigating nrG-1 have been performed using a variety of methods, including in vitro models, and animal and human clinical trials; however, the results are not consistent. nrG-1

show abstract

Localization and dynamic changes of neuregulin‐1 at C‐type synaptic boutons in association with motor neuron injury and repair

Cited by 27 publications

References 74 publications

Cholinergic neuroplasticity in asthma driven by TrkB signaling

Cholinergic neuroplasticity in asthma driven by TrkB signaling

Intramuscular Botulinum toxin A injections induce central changes to axon initial segments and cholinergic boutons on spinal motoneurones in rats

Neuregulin‑1: An underlying protective force of cardiac dysfunction in sepsis (Review)

Contact Info

Product

Resources

About