scholarly journals Postsynaptic CaV1.1-driven calcium signaling coordinates presynaptic differentiation at the developing neuromuscular junction

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Mehmet Mahsum Kaplan ◽  
Bernhard E. Flucher
Keyword(s):  
Neuromuscular Junction ◽  
Calcium Signaling ◽  
Motor Neurons ◽  
Motor Nerve ◽  
Neuromuscular Synapse ◽  
Presynaptic Differentiation ◽  
Motor Nerves ◽  
Muscle Calcium ◽  
Activity Dependent ◽  
Postsynaptic Target

AbstractProper formation of neuromuscular synapses requires the reciprocal communication between motor neurons and muscle cells. Several anterograde and retrograde signals involved in neuromuscular junction formation are known. However the postsynaptic mechanisms regulating presynaptic differentiation are still incompletely understood. Here we report that the skeletal muscle calcium channel (CaV1.1) is required for motor nerve differentiation and that the mechanism by which CaV1.1 controls presynaptic differentiation utilizes activity-dependent calcium signaling in muscle. In mice lacking CaV1.1 or CaV1.1-driven calcium signaling motor nerves are ectopically located and aberrantly defasciculated. Axons fail to recognize their postsynaptic target structures and synaptic vesicles and active zones fail to correctly accumulate at the nerve terminals opposite AChR clusters. These presynaptic defects are independent of aberrant AChR patterning and more sensitive to deficient calcium signals. Thus, our results identify CaV1.1-driven calcium signaling in muscle as a major regulator coordinating multiple aspects of presynaptic differentiation at the neuromuscular synapse.

scholarly journals The p75NTR neurotrophin receptor is required to organize the mature neuromuscular synapse by regulating synaptic vesicle availability

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Viviana Pérez ◽  
Francisca Bermedo-Garcia ◽  
Diego Zelada ◽  
Felipe A. Court ◽  
Miguel Ángel Pérez ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Neuronal Damage ◽  
Neuromuscular Synapse ◽  
Force Production ◽  
Synaptic Function ◽  
Neurotrophin Receptor ◽  
Acetylcholinesterase Inhibition ◽  
Pharmacological Intervention

Abstract The coordinated movement of organisms relies on efficient nerve-muscle communication at the neuromuscular junction. After peripheral nerve injury or neurodegeneration, motor neurons and Schwann cells increase the expression of the p75NTR pan-neurotrophin receptor. Even though p75NTR targeting has emerged as a promising therapeutic strategy to delay peripheral neuronal damage progression, the effects of long-term p75NTR inhibition at the mature neuromuscular junction have not been elucidated. We performed quantitative neuroanathomical analyses of the neuromuscular junction in p75NTR null mice by laser confocal and electron microscopy, which were complemented with electromyography, locomotor tests, and pharmacological intervention studies. Mature neuromuscular synapses of p75NTR null mice show impaired postsynaptic organization and ultrastructural complexity, which correlate with altered synaptic function at the levels of nerve activity-induced muscle responses, muscle fiber structure, force production, and locomotor performance. Our results on primary myotubes and denervated muscles indicate that muscle-derived p75NTR does not play a major role on postsynaptic organization. In turn, motor axon terminals of p75NTR null mice display a strong reduction in the number of synaptic vesicles and active zones. According to the observed pre and postsynaptic defects, pharmacological acetylcholinesterase inhibition rescued nerve-dependent muscle response and force production in p75NTR null mice. Our findings revealing that p75NTR is required to organize mature neuromuscular junctions contribute to a comprehensive view of the possible effects caused by therapeutic attempts to target p75NTR.

scholarly journals Single Cell Deconstruction of Muscle Stem Cell Heterogeneity During Aging Reveals Sensitivity to the Neuromuscular Junction

2020 ◽  
Author(s):  
Peter J. Ulintz ◽  
Jacqueline Larouche ◽  
Mahir Mohiuddin ◽  
Jesus Castor Macias ◽  
Sarah J. Kurpiers ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Single Cell ◽  
Motor Neurons ◽  
Satellite Cells ◽  
Neural Control ◽  
Neuromuscular Diseases ◽  
Neuromuscular Synapse ◽  
List Type ◽  
Genetic Rescue ◽  
Before And After

AbstractDuring aging and neuromuscular diseases, there is a progressive loss of skeletal muscle volume and function in that impacts mobility and quality of life. Muscle loss is often associated with denervation and a loss of resident muscle stem cells (satellite cells or MuSCs), but the relationship between MuSCs and neural control has not been established. Herein, using a combination of single-cell transcriptomic analysis, high-resolution immunofluorescence imaging and transgenic young and aged mice as well as from mice with neuromuscular degeneration (Sod1-/-), a compensatory neuro-responsive function for a subset of MuSCs was identified. Genetic rescue of motor neurons in Sod1-/- mice reduced this subset of MuSCs and restored integrity of the neuromuscular junction (NMJ) in a manner akin to young muscle. Administration of severe neuromuscular trauma induced young MuSCs to specifically engraft in a position proximal to the NMJ but in aging, this behavior was abolished. Contrasting the expression programs of young and aged MuSCs after muscle injury at the single cell level, we observed distinctive gene expression programs between responses to neuro-muscular degeneration and muscle trauma. Collectively, these data reveal MuSCs sense synaptic perturbations during aging and neuro-muscular deterioration, and can exert support for the NMJ, particularly in young muscle.HighlightsTranscriptional landscapes of single satellite cells from different ages before and after injury as well as neurodegenerative models before and after nervous rescueA population of satellite cells reside in close proximity to neuromuscular synapse, which are lost with ageDenervation promotes satellite cell engraftment into post-synaptic regions of young as opposed to aged muscle

scholarly journals Aberrant Morphology and Residual Transmitter Release at the Munc13-Deficient Mouse Neuromuscular Synapse

2005 ◽  
Vol 25 (14) ◽  
pp. 5973-5984 ◽  
Author(s):  
Frédérique Varoqueaux ◽  
Michèle S. Sons ◽  
Jaap J. Plomp ◽  
Nils Brose
Keyword(s):  
Neuromuscular Junction ◽  
Synaptic Vesicle ◽  
Motor Neurons ◽  
Transmitter Release ◽  
Hippocampal Neurons ◽  
Neuromuscular Junctions ◽  
Neuromuscular Synapse ◽  
Synaptic Activity ◽  
Neuromuscular Synaptogenesis ◽  
Deficient Mice

ABSTRACT In cultured hippocampal neurons, synaptogenesis is largely independent of synaptic transmission, while several accounts in the literature indicate that synaptogenesis at cholinergic neuromuscular junctions in mammals appears to partially depend on synaptic activity. To systematically examine the role of synaptic activity in synaptogenesis at the neuromuscular junction, we investigated neuromuscular synaptogenesis and neurotransmitter release of mice lacking all synaptic vesicle priming proteins of the Munc13 family. Munc13-deficient mice are completely paralyzed at birth and die immediately, but form specialized neuromuscular endplates that display typical synaptic features. However, the distribution, number, size, and shape of these synapses, as well as the number of motor neurons they originate from and the maturation state of muscle cells, are profoundly altered. Surprisingly, Munc13-deficient synapses exhibit significantly increased spontaneous quantal acetylcholine release, although fewer fusion-competent synaptic vesicles are present and nerve stimulation-evoked secretion is hardly elicitable and strongly reduced in magnitude. We conclude that the residual transmitter release in Munc13-deficient mice is not sufficient to sustain normal synaptogenesis at the neuromuscular junction, essentially causing morphological aberrations that are also seen upon total blockade of neuromuscular transmission in other genetic models. Our data confirm the importance of Munc13 proteins in synaptic vesicle priming at the neuromuscular junction but indicate also that priming at this synapse may differ from priming at glutamatergic and γ-aminobutyric acid-ergic synapses and is partly Munc13 independent. Thus, non-Munc13 priming proteins exist at this synapse or vesicle priming occurs in part spontaneously: i.e., without dedicated priming proteins in the release machinery.

scholarly journals KATP channels and NO dilate redundantly intramuscular arterioles during electrical stimulation of the skeletal muscle in mice

2021 ◽  
Author(s):  
Simon Schemke ◽  
Cor de Wit
Keyword(s):  
Skeletal Muscle ◽  
Electrical Stimulation ◽  
Motor Nerve ◽  
Neuromuscular Synapse ◽  
Katp Channels ◽  
Neuromuscular Synapses ◽  
Maximal Diameter ◽  
Motor Nerves ◽  
A Minor ◽  
Stimulation Of

AbstractFunctional hyperemia is fundamental to provide enhanced oxygen delivery during exercise in skeletal muscle. Different mechanisms are suggested to contribute, mediators from skeletal muscle, transmitter spillover from the neuromuscular synapse as well as endothelium-related dilators. We hypothesized that redundant mechanisms that invoke adenosine, endothelial autacoids, and KATP channels mediate the dilation of intramuscular arterioles in mice. Arterioles (maximal diameter: 20–42 µm, n = 65) were studied in the cremaster by intravital microscopy during electrical stimulation of the motor nerve to induce twitch or tetanic skeletal muscle contractions (10 or 100 Hz). Stimulation for 1–60 s dilated arterioles rapidly up to 65% of dilator capacity. Blockade of nicotinergic receptors blocked muscle contraction and arteriolar dilation. Exclusive blockade of adenosine receptors (1,3-dipropyl-8-(p-sulfophenyl)xanthine) or of NO and prostaglandins (nitro-L-arginine and indomethacin, LN + Indo) exerted only a minor attenuation. Combination of these blockers, however, reduced the dilation by roughly one-third during longer stimulation periods (> 1 s at 100 Hz). Blockade of KATP channels (glibenclamide) which strongly reduced adenosine-induced dilation reduced responses upon electrical stimulation only moderately. The attenuation was strongly enhanced if glibenclamide was combined with LN + Indo and even observed during brief stimulation. LN was more efficient than indomethacin to abrogate dilations if combined with glibenclamide. Arteriolar dilations induced by electrical stimulation of motor nerves require muscular contractions and are not elicited by acetylcholine spillover from neuromuscular synapses. The dilations are mediated by redundant mechanisms, mainly activation of KATP channels and release of NO. The contribution of K+ channels and hyperpolarization sets the stage for ascending dilations that are crucial for a coordinated response in the network.

Synaptic connections between motor neurons and interneurons in the fourth thoracic ganglion of the crayfish, Procambarus clarkii

1989 ◽  
Vol 62 (6) ◽  
pp. 1237-1250 ◽  
Author(s):  
A. Chrachri ◽  
F. Clarac
Keyword(s):  
Motor Neurons ◽  
Cobalt Chloride ◽  
Procambarus Clarkii ◽  
Lucifer Yellow ◽  
Motor Nerve ◽  
Thoracic Ganglion ◽  
Synaptic Connections ◽  
Motor Patterns ◽  
Antagonist Muscles ◽  
Motor Nerves

1. A new preparation of the thoracic nervous system of the crayfish, Procambarus clarkii, has been developed, in which it is possible to work with identified members of motor neuronal pools. 2. In such a preparation, it is possible to dissect all specific proximal motor nerves (protractor, retractor, anterior elevator, posterior elevator, and depressor). Motor neurons innervating the four proximal muscles of the fourth walking leg have been identified both physiologically and anatomically by staining the recorded motor neuron with Lucifer yellow through the microelectrode. 3. By the use of cobalt chloride, we have mapped the distribution of somata of all motor neurons within the fourth thoracic ganglion that innervate the different groups of muscles controlling the movement of the fourth walking leg. 4. Most motor neurons innervating the same muscle seem to be electrically coupled, except some depressor motor neurons. 5. Motor neurons innervating antagonist muscles are linked by inhibitory connections. These connections are reciprocal for protractor and retractor motor neurons but usually not reciprocal between elevator and depressor motor neurons. 6. Walking interneurons were identified as neurons without axons in any motor nerve, which modified the motor neuronal activity. Some of them have been injected with Lucifer yellow. 7. Some interneurons make synaptic connections only with antagonist motor neurons that control the movement of one joint. Probably their functional role is to reinforce or to limit the antagonism between each pair of antagonist motor neurons. 8. Other interneurons make synaptic connections with motor neurons innervating muscles controlling different leg joints. These interneurons may play a role in generating the motor patterns that underlie forward and backward walking.

Axonal Growth Abnormalities Underlying Ocular Cranial Nerve Disorders

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Mary C. Whitman
Keyword(s):  
Axon Guidance ◽  
Motor Neurons ◽  
Motor Nerve ◽  
Axon Growth ◽  
Annual Review ◽  
Publication Date ◽  
Causative Gene ◽  
Axon Targeting ◽  
Vision Science ◽  
Motor Nerves

Abnormalities in cranial motor nerve development cause paralytic strabismus syndromes, collectively referred to as congenital cranial dysinnervation disorders, in which patients cannot fully move their eyes. These disorders can arise through one of two mechanisms: ( a) defective motor neuron specification, usually by loss of a transcription factor necessary for brainstem patterning, or ( b) axon growth and guidance abnormalities of the oculomotor, trochlear, and abducens nerves. This review focuses on our current understanding of axon guidance mechanisms in the cranial motor nerves and how disease-causing mutations disrupt axon targeting. Abnormalities of axon growth and guidance are often limited to a single nerve or subdivision, even when the causative gene is ubiquitously expressed. Additionally, when one nerve is absent, its normal target muscles attract other motor neurons. Study of these disorders highlights the complexities of axon guidance and how each population of neurons uses a unique but overlapping set of axon guidance pathways. Expected final online publication date for the Annual Review of Vision Science, Volume 7 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Comparison of neuromuscular junction dynamics following ischemic and aged skeletal muscle

2021 ◽  
Author(s):  
Berna Aliya ◽  
Mahir Mohiuddin ◽  
Jeongmoon Choi ◽  
Gunjae Jeong ◽  
Innie Kang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Neuromuscular Junction ◽  
Motor Neurons ◽  
Acetylcholine Receptors ◽  
Neuromuscular Diseases ◽  
Neuromuscular Synapse ◽  
Imaging Method ◽  
Aging Condition ◽  
Neuromuscular Synapses ◽  
Neuronal Degradation

Both aging and neuromuscular diseases lead to significant changes in the morphology and functionality of the neuromuscular synapse. Skeletal muscles display a remarkable regenerative capacity, however, are still susceptible to diseases of aging and peripheral nerve perturbations. In this study, we assessed how neuromuscular synapses differ in aged and injured skeletal muscle using an improved neuromuscular junction (NMJ) staining and imaging method. We found that both aged and ischemic skeletal muscle display Wallerian degeneration of the presynaptic motor axons and fragmentation of postsynaptic acetylcholine receptors (AChRs). Quantifiable measurements of various metrics of the NMJs provide a more concrete idea of the dynamics that are occurring in the muscle microenvironment. We questioned whether neuronal degradation precedes myofiber atrophy or vice versa. Previously, it was shown that a cellular crosstalk exists among the motor neurons, myofibers, vasculature, and mitochondria within the muscle microdomain. It is apparent that lack of blood flow to motor neurons in ischemic skeletal muscle disrupts the structure of NMJs, however it is unclear if the aging condition experiences similar dynamics. We demonstrated that both aged and ischemic skeletal muscle demonstrate similar patterns of degeneration, characterized by a smaller percentage overlap of presynaptic and postsynaptic sides, greater fragmentation of AChRs, and a smaller area of AChR clusters. Together, these results reveal high resolution, precise parallels between the aged and ischemic NMJs.

Androgen-induced plasticity at a “vocal” neuromuscular synapse

1994 ◽  
Vol 52 ◽  
pp. 32-33
Author(s):  
Darcy B. Kelley ◽  
Martha L. Tobias ◽  
Mark Ellisman
Keyword(s):  
Xenopus Laevis ◽  
Motor Neurons ◽  
Sexual Differentiation ◽  
Molecular Basis ◽  
Neuromuscular Synapse ◽  
Sexually Dimorphic ◽  
Intracellular Protein ◽  
Developmental Program ◽  
Androgen Action ◽  
Clawed Frog

Brain and muscle are sexually differentiated tissues in which masculinization is controlled by the secretion of androgens from the testes. Sensitivity to androgen is conferred by the expression of an intracellular protein, the androgen receptor. A central problem of sexual differentiation is thus to understand the cellular and molecular basis of androgen action. We do not understand how hormone occupancy of a receptor translates into an alteration in the developmental program of the target cell. Our studies on sexual differentiation of brain and muscle in Xenopus laevis are designed to explore the molecular basis of androgen induced sexual differentiation by examining how this hormone controls the masculinization of brain and muscle targets.Our approach to this problem has focused on a highly androgen sensitive, sexually dimorphic neuromuscular system: laryngeal muscles and motor neurons of the clawed frog, Xenopus laevis. We have been studying sex differences at a synapse, the laryngeal neuromuscular junction, which mediates sexually dimorphic vocal behavior in Xenopus laevis frogs.

scholarly journals Bioengineered model of the human motor unit with physiologically functional neuromuscular junctions

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rowan P. Rimington ◽  
Jacob W. Fleming ◽  
Andrew J. Capel ◽  
Patrick C. Wheeler ◽  
Mark P. Lewis
Keyword(s):  
Neuromuscular Junction ◽  
Motor Neuron ◽  
Motor Unit ◽  
Motor Nerve ◽  
Motor Units ◽  
Extracellular Matrices ◽  
Synaptic Membrane ◽  
Type I ◽  
Dependent Manner ◽  
Human Motor

AbstractInvestigations of the human neuromuscular junction (NMJ) have predominately utilised experimental animals, model organisms, or monolayer cell cultures that fail to represent the physiological complexity of the synapse. Consequently, there remains a paucity of data regarding the development of the human NMJ and a lack of systems that enable investigation of the motor unit. This work addresses this need, providing the methodologies to bioengineer 3D models of the human motor unit. Spheroid culture of iPSC derived motor neuron progenitors augmented the transcription of OLIG2, ISLET1 and SMI32 motor neuron mRNAs ~ 400, ~ 150 and ~ 200-fold respectively compared to monolayer equivalents. Axon projections of adhered spheroids exceeded 1000 μm in monolayer, with transcription of SMI32 and VACHT mRNAs further enhanced by addition to 3D extracellular matrices in a type I collagen concentration dependent manner. Bioengineered skeletal muscles produced functional tetanic and twitch profiles, demonstrated increased acetylcholine receptor (AChR) clustering and transcription of MUSK and LRP4 mRNAs, indicating enhanced organisation of the post-synaptic membrane. The number of motor neuron spheroids, or motor pool, required to functionally innervate 3D muscle tissues was then determined, generating functional human NMJs that evidence pre- and post-synaptic membrane and motor nerve axon co-localisation. Spontaneous firing was significantly elevated in 3D motor units, confirmed to be driven by the motor nerve via antagonistic inhibition of the AChR. Functional analysis outlined decreased time to peak twitch and half relaxation times, indicating enhanced physiology of excitation contraction coupling in innervated motor units. Our findings provide the methods to maximise the maturity of both iPSC motor neurons and primary human skeletal muscle, utilising cell type specific extracellular matrices and developmental timelines to bioengineer the human motor unit for the study of neuromuscular junction physiology.

Sign in / Sign up

Export Citation Format

Share Document