scholarly journals Glutamate at the Vertebrate Neuromuscular Junction: From Modulation to Neurotransmission

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 996 ◽  
Author(s):  
Colombo ◽  
Francolini
Keyword(s):  
Neuromuscular Junction ◽  
Signaling Pathways ◽  
Muscle Fiber ◽  
Neuromuscular Junctions ◽  
Motor Nerve ◽  
Vertebrate Development ◽  
Motor Nerve Ending ◽  
Downstream Signaling ◽  
Synaptic Neurotransmission ◽  
Synaptic Receptors

Although acetylcholine is the major neurotransmitter operating at the skeletal neuromuscular junction of many invertebrates and of vertebrates, glutamate participates in modulating cholinergic transmission and plastic changes in the last. Presynaptic terminals of neuromuscular junctions contain and release glutamate that contribute to the regulation of synaptic neurotransmission through its interaction with pre- and post-synaptic receptors activating downstream signaling pathways that tune synaptic efficacy and plasticity. During vertebrate development, the chemical nature of the neurotransmitter at the vertebrate neuromuscular junction can be experimentally shifted from acetylcholine to other mediators (including glutamate) through the modulation of calcium dynamics in motoneurons and, when the neurotransmitter changes, the muscle fiber expresses and assembles new receptors to match the nature of the new mediator. Finally, in adult rodents, by diverting descending spinal glutamatergic axons to a denervated muscle, a functional reinnervation can be achieved with the formation of new neuromuscular junctions that use glutamate as neurotransmitter and express ionotropic glutamate receptors and other markers of central glutamatergic synapses. Here, we summarize the past and recent experimental evidences in support of a role of glutamate as a mediator at the synapse between the motor nerve ending and the skeletal muscle fiber, focusing on the molecules and signaling pathways that are present and activated by glutamate at the vertebrate neuromuscular junction.

scholarly journals Effects of Vocal Training on Thyroarytenoid Muscle Neuromuscular Junctions and Myofibers in Young and Older Rats

2020 ◽  
Author(s):  
Adrianna C Shembel ◽  
Charles Lenell ◽  
Sophia Chen ◽  
Aaron M Johnson
Keyword(s):  
Neuromuscular Junction ◽  
Muscle Fiber ◽  
Acoustic Analysis ◽  
Neuromuscular Junctions ◽  
Fiber Type ◽  
Male Rats ◽  
Brown Norway ◽  
Control Group ◽  
Vocal Training ◽  
Thyroarytenoid Muscle

Abstract The purpose of this investigation was to determine the effects of vocal training on neuromuscular junction (NMJ) morphology and muscle fiber size and composition in the thyroarytenoid muscle, the primary muscle in the vocal fold, in younger (9-month) and older (24-month) Fischer 344 × Brown Norway male rats. Over 4 or 8 weeks of vocal training, rats of both ages progressively increased their daily number of ultrasonic vocalizations (USVs) through operant conditioning and were then compared to an untrained control group. Neuromuscular junction morphology and myofiber size and composition were measured from the thyroarytenoid muscle. Acoustic analysis of USVs before and after training quantified the functional effect of training. Both 4- and 8-week training resulted in less NMJ motor endplate dispersion in the lateral portion of the thyroarytenoid muscle in rats of both ages. Vocal training and age had no significant effects on laryngeal myofiber size or type. Vocal training resulted in a greater number of USVs with longer duration and increased intensity. This study demonstrated that vocal training induces laryngeal NMJ morphology and acoustic changes. The lack of significant effects of vocal training on muscle fiber type and size suggests vocal training significantly improves neuromuscular efficiency but does not significantly influence muscle strength changes.

scholarly journals The Neuromuscular Junction in Health and Disease: Molecular Mechanisms Governing Synaptic Formation and Homeostasis

2020 ◽  
Vol 13 ◽  
Author(s):  
Pedro M. Rodríguez Cruz ◽  
Judith Cossins ◽  
David Beeson ◽  
Angela Vincent
Keyword(s):  
Neuromuscular Junction ◽  
Action Potential ◽  
Motor Neuron ◽  
Muscle Fiber ◽  
Neuromuscular Transmission ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Motor Nerve ◽  
And Function

The neuromuscular junction (NMJ) is a highly specialized synapse between a motor neuron nerve terminal and its muscle fiber that are responsible for converting electrical impulses generated by the motor neuron into electrical activity in the muscle fibers. On arrival of the motor nerve action potential, calcium enters the presynaptic terminal, which leads to the release of the neurotransmitter acetylcholine (ACh). ACh crosses the synaptic gap and binds to ACh receptors (AChRs) tightly clustered on the surface of the muscle fiber; this leads to the endplate potential which initiates the muscle action potential that results in muscle contraction. This is a simplified version of the events in neuromuscular transmission that take place within milliseconds, and are dependent on a tiny but highly structured NMJ. Much of this review is devoted to describing in more detail the development, maturation, maintenance and regeneration of the NMJ, but first we describe briefly the most important molecules involved and the conditions that affect their numbers and function. Most important clinically worldwide, are myasthenia gravis (MG), the Lambert-Eaton myasthenic syndrome (LEMS) and congenital myasthenic syndromes (CMS), each of which causes specific molecular defects. In addition, we mention the neurotoxins from bacteria, snakes and many other species that interfere with neuromuscular transmission and cause potentially fatal diseases, but have also provided useful probes for investigating neuromuscular transmission. There are also changes in NMJ structure and function in motor neuron disease, spinal muscle atrophy and sarcopenia that are likely to be secondary but might provide treatment targets. The NMJ is one of the best studied and most disease-prone synapses in the nervous system and it is amenable to in vivo and ex vivo investigation and to systemic therapies that can help restore normal function.

scholarly journals Adrenoceptors Modulate Cholinergic Synaptic Transmission at the Neuromuscular Junction

2021 ◽  
Vol 22 (9) ◽  
pp. 4611
Author(s):  
Ellya Bukharaeva ◽  
Venera Khuzakhmetova ◽  
Svetlana Dmitrieva ◽  
Andrei Tsentsevitsky
Keyword(s):  
Neuromuscular Junction ◽  
Neurodegenerative Diseases ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Acetylcholine Release ◽  
Neuromuscular Junctions ◽  
Motor Nerve ◽  
Nerve Terminals ◽  
Adrenergic Agents ◽  
Cholinergic Synaptic Transmission

Adrenoceptor activators and blockers are widely used clinically for the treatment of cardiovascular and pulmonary disorders. More recently, adrenergic agents have also been used to treat neurodegenerative diseases. Recent studies indicate a location of sympathetic varicosities in close proximity to neuromuscular junctions. The pressing question is whether there could be any effects of endo- or exogenous catecholamines on cholinergic neuromuscular transmission. It was shown that the pharmacological stimulation of adrenoceptors, as well as sympathectomy, can affect both acetylcholine release from motor nerve terminals and the functioning of postsynaptic acetylcholine receptors. In this review, we discuss the recent data regarding the effects of adrenergic drugs on neurotransmission at the neuromuscular junction. The elucidation of the molecular mechanisms by which the clinically relevant adrenomimetics and adrenoblockers regulate quantal acetylcholine release from the presynaptic nerve terminals and postsynaptic sensitivity may help in the design of highly effective and well-tolerated sympathomimetics for treating a number of neurodegenerative diseases accompanied by synaptic defects.

Degenerative changes in the function of neuromuscular junctions of Manduca sexta during metamorphosis

1992 ◽  
Vol 167 (1) ◽  
pp. 61-89
Author(s):  
I. M. Sonea ◽  
M. B. Rheuben
Keyword(s):  
Manduca Sexta ◽  
Muscle Fiber ◽  
Neuromuscular Junctions ◽  
Motor Nerve ◽  
Normal Function ◽  
Degenerative Changes ◽  
Resting Potential ◽  
Morphological Evidence ◽  
Low Frequencies ◽  
Cable Properties

In Manduca sexta the decline in neuromuscular function during metamorphic degeneration was compared in two muscles which differed characteristically with regard to pre- and postsynaptic physiological properties. In both muscles, morphological evidence indicated that a significant number of the active zones within the population of neuromuscular junctions on a given fiber were nonfunctional. Nevertheless, the degenerating nerve terminals were able to produce an above-threshold excitatory junction potential (EJP) which was facilitated in a manner characteristic of the muscle being observed. Abnormal findings during the early stages of degeneration included a larger than normal EJP, a decline in EJP amplitude over a 20 min period even with low frequencies of stimulation, an increase in EJP duration, a decline in muscle fiber resting potential amplitude with age, a decrease or disappearance of post-tetanic potentiation and long-term facilitation, and an increased likelihood that the motor nerve would fail to conduct a stimulus. The two muscles were qualitatively similar but quantitatively different with regard to these degenerative changes. It is suggested that this combination of relatively normal function with abnormal properties might be associated with the withdrawal of glial processes from the neuromuscular junctions, changes in the cable properties associated with shrivelling of the muscle fibers, and a decline in the metabolic functions supporting both muscle fiber resting potentials and those underlying transmitter synthesis, mobilization and release.

scholarly journals Neuromuscular Junctions in Flight and Tymbal Muscles of the Cicada

1958 ◽  
Vol 4 (3) ◽  
pp. 251-256 ◽  
Author(s):  
George A. Edwards ◽  
Helmut Ruska ◽  
Étienne de Harven
Keyword(s):  
Endoplasmic Reticulum ◽  
Neuromuscular Junction ◽  
Muscle Fiber ◽  
High Frequency ◽  
Plasma Membranes ◽  
Flight Muscle ◽  
Neuromuscular Junctions ◽  
Muscle Fibers ◽  
Membrane System ◽  
Indirect Flight Muscle

The tymbal muscle fiber in the cicada closely resembles the indirect flight muscle fiber in its structural detail. We agree with other authors that the tymbal muscle is a modified indirect flight muscle. The peripheral nerve branches to the tymbal and flight muscle fibers are similar to those in the wasp leg. The axon is loosely mantled by irregular turns of the mesaxon, enclosing cytoplasm. The nerve is therefore a tunicated nerve. The neuromuscular junction in the high frequency muscle fibers shows direct apposition of plasma membranes of axon and muscle fiber, large numbers of mitochondria and synaptic vesicles in the axon, and concentrations of mitochondria, aposynaptic granules, and endoplasmic reticulum in the postsynaptic area of the muscle fiber. Of special interest is the multitude of intracellular, opposing membranes in the postsynaptic area. They form laminated stacks and whorls, vesicles, cysternae, and tubules. They occasionally show continuity with the plasma membrane, the outer nuclear envelope, and the circumfibrillar endoplasmic reticulum. The membrane system in this area is designated "rete synapticum." It is believed to add to the electrical capacity of the neuromuscular junction, to serve in transmission of potentials, and possibly is the site of the oscillating mechanism in high-frequency muscle fibers.

scholarly journals Voltage-Dependent P/Q-Type Calcium Channels at the Frog Neuromuscular Junction

2011 ◽  
pp. 815-823 ◽  
Author(s):  
L. F. NURULLIN ◽  
A. R. MUKHITOV ◽  
A. N. TSENTSEVYTSKY ◽  
N. V. PETROVA ◽  
D. V. SAMIGULLIN ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Calcium Channels ◽  
Motor Nerve ◽  
Calcium Transient ◽  
Functional Expression ◽  
Frog Neuromuscular Junction ◽  
Motor Nerve Ending ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Release Of Acetylcholine

It is well known that antagonists of N-type voltage-gated calcium channels inhibit the evoked quantal release of acetylcholine in amphibian neuromuscular synapses. This, however, does not exclude the functional expression of other types of voltage-gated calcium channels in these nerve terminals. Using immunocytochemistry, we detected the expression of the 1A subunit of P/Q-type calcium channels (that is otherwise typical of mammalian motor nerve endings) in the frog neuromuscular junction. In addition, we demonstrated that the P/Q-type channel blocker ω-agatoxin IVA (20 nM) reduced the action potential-induced calcium transient and significantly decreased both spontaneous and evoked mediator release. Our data indicates the functional expression of P/Q-type calcium channels in the frog motor nerve ending which participate in acetylcholine release.

scholarly journals Degenerative changes in the structure of neuromuscular junctions of Manduca sexta during metamorphosis

1992 ◽  
Vol 167 (1) ◽  
pp. 119-154
Author(s):  
M. B. Rheuben
Keyword(s):  
Manduca Sexta ◽  
Muscle Fiber ◽  
Nerve Terminal ◽  
Structural Changes ◽  
Neuromuscular Junctions ◽  
Motor Nerve ◽  
Freeze Fracture ◽  
Outer Region ◽  
Peripheral Region ◽  
Phagocytic Cells

During the degenerative processes that precede and accompany metamorphosis of the larval mesothoracic dorsal longitudinal muscles of Manduca sexta, the motor nerves and neuromuscular junctions undergo a variety of structural changes that are largely secondary to the changing morphologies of their respective glia. In the central region of the main motor nerve, the multiple layers of glial processes surrounding each of the large axons withdraw, leaving them apposed. In the peripheral region of the main motor nerve and in the secondary and tertiary nerve branches supplying the muscle, the outer glial processes of the nerve sheath and those that loosely wrap accompanying small neurosecretory axons all swell. Phagocytic cells and cells of unknown function invade the outer region of the nerve. In the neuromuscular junctions, the glial cells withdraw their processes from a complicated interdigitation with processes from the muscle fiber and from their relationship with the nerve terminal. As degeneration proceeds, this allows a greater area of contact between each nerve terminal and the muscle fiber. Within each junction there is a mixture of both functional and non-functional regions and active zones, as determined by both thin-section and freeze-fracture observations. No correlation was found between the degree of degeneration of a neuromuscular junction and its association with a particular muscle fiber or its position on the fiber relative to the origin or insertion.

Transmitter packaging at frog neuromuscular junctions exposed to anticholinesterases; the role of second-stage acetylcholine loading

1996 ◽  
Vol 76 (4) ◽  
pp. 2614-2625 ◽  
Author(s):  
L. A. Naves ◽  
W. Van der Kloot
Keyword(s):  
Neuromuscular Junction ◽  
Synaptic Vesicles ◽  
Time Course ◽  
Neuromuscular Junctions ◽  
Motor Nerve ◽  
Ache Inhibitor ◽  
Motor Nerve Terminal ◽  
Unexpected Finding ◽  
Extracellular Solution ◽  
Second Stage

1. This investigation was undertaken to explore an unexpected effect of vesamicol, an agent that inhibits active acetylcholine (ACh) uptake into isolated synaptic vesicles. Previous studies at the neuromuscular junction showed that vesamicol makes miniature end-plate currents (MEPCs) smaller only after tens of thousands of quanta have been released. Inhibiting acetylcholinesterase (AChE) makes the MEPCs larger than normal. Our unexpected finding was that with the AChE inhibitor present, adding 2 microM (-)-vesamicol decreases the size of the MEPCs by approximately 30%. The decrease was apparent within 15-30 min, during which only a few thousand quanta had been released. 2. Experimental tests showed that the (-)-vesamicol treatment is unlikely to be acting postsynaptically. For example, it did not slow the rise of MEPCs, which would occur if the endplate receptors were blocked. 3. When AChE was inhibited, three treatments expected to block active choline (Ch) uptake into the presynaptic terminals decreased MEPC size: 1) elevating extracellular K+ to diminish the Na+ electrochemical gradient required for Ch uptake; 2) replacing extracellular Na+ with methylamine+; and 3) adding hemicholinium-3 (HC-3), an inhibitor of the Ch transporter. These treatments did not act by reactivating AChE, blocking the endplate ACh receptor, or by enhancing the desensitization of the ACh receptor. 4. Previous evidence suggests that synaptic vesicles are formed and partially filled with ACh in the cytoplasm and then receive additional ACh when they attach to the active zones, a process that is called second-stage loading. We conclude that the MEPCs are becoming smaller when second-stage loading is blocked by (-)-vesamicol or when the supply of ACh in the cytoplasm of the motor nerve terminal is depleted. 5. To follow the time course of second-stage loading, we used the false transmitter precursor monoethylcholine (MECh). It enters the terminal and is transformed into acetylmonoethylcholine (AMECh). When 200 microM MECh was placed in the extracellular solution and the AChE was inhibited, MEPC size was significantly smaller after 10 min. MEPC size increased once again over a period of time when MECh was removed from the extracellular solution and replaced with Ch. 6. We conclude that at the neuromuscular junction second-stage loading is responsible for loading a significant fraction of the ACh into the quanta.

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