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Structure and Function of the Mammalian Neuromuscular Junction

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Abstract

The mammalian neuromuscular junction (NMJ) comprises a presynaptic terminal, a postsynaptic receptor region on the muscle fiber (endplate), and the perisynaptic (terminal) Schwann cell. As with any synapse, the purpose of the NMJ is to transmit signals from the nervous system to muscle fibers. This neural control of muscle fibers is organized as motor units, which display distinct structural and functional phenotypes including differences in pre‐ and postsynaptic elements of NMJs. Motor units vary considerably in the frequency of their activation (both motor neuron discharge rate and duration/duty cycle), force generation, and susceptibility to fatigue. For earlier and more frequently recruited motor units, the structure and function of the activated NMJs must have high fidelity to ensure consistent activation and continued contractile response to sustain vital motor behaviors (e.g., breathing and postural balance). Similarly, for higher force less frequent behaviors (e.g., coughing and jumping), the structure and function of recruited NMJs must ensure short‐term reliable activation but not activation sustained for a prolonged period in which fatigue may occur. The NMJ is highly plastic, changing structurally and functionally throughout the life span from embryonic development to old age. The NMJ also changes under pathological conditions including acute and chronic disease. Such neuroplasticity often varies across motor unit types. © 2022 American Physiological Society. Compr Physiol 12:1‐36, 2022.

Figure 1. Figure 1. For a given level of glutamatergic input current (Isyn), the change in membrane potential (dVm/dt) will be greater for smaller motor neurons due to their lower membrane capacitance (size; Cm) and higher input resistance (Rin) compared to larger motor neurons. Thus, smaller motor neurons will reach the threshold for action potential generation sooner (i.e., earlier recruitment) than larger motor neurons. Smaller motor neurons also have smaller axons with slower action potential propagation velocities compared to larger motor neurons. These relationships constitute the Henneman's size principle for motor unit recruitment.
Figure 2. Figure 2. (A) Imaging of the phrenic motor neuron pool from rats acquired by confocal microscopy after labeling with tetramethylrhodamine‐dextran (nerve‐dip) or cholera toxin B (CTB) injected into the intrapleural space. Reused, with permission, from Mantilla CB, et al., 2009/ELSEVIER 279. (B) The distribution of phrenic motor neuron somal surface areas divided into tertiles. (C) Smaller motor neurons comprise slow (S; type I muscle fibers) and fast, fatigue‐resistant (FR; type IIa muscle fibers) motor units, whereas larger motor neurons comprise fast fatigue intermediate (FInt; type IIx muscle fibers) and fast fatigable (FF; type IIb muscle fibers). (D) In the rat diaphragm muscle (DIAm), a model predicting motor unit recruitment during different motor behaviors was developed based on (i) a recruitment order dependent on motor neuron size (S first FF last), (ii) the forces generated by each motor unit type, and (iii) the relative proportion of each motor unit type. The model predictions were compared to the transdiaphragmatic pressure (Pdi) or force generated by the DIAm 273. Based on this model, the lower Pdi generated during quiet breathing (eupnea) and hypercapnia/hypoxia stimulated breathing required the recruitment of only fatigue‐resistant S and FR motor units. In contrast, with more forceful (higher Pdi) DIAm efforts (e.g., coughing/sneezing and voiding) require recruitment of the entire phrenic motor neuron pool, including more fatigable FInt and FF motor units.
Figure 3. Figure 3. (A) Fiber‐type classification in the rat diaphragm muscle (DIAm) is based on immunoreactivity to primary antibodies for myosin heavy chain (MyHC) isoforms (pseudo‐colored in this example). Reused, with permission, from Mantilla CB, et al., 2010/ELSEVIER 273. (B) Composite table based on results from a number of studies displaying mean ± SD of muscle fiber cross‐sectional area, the proportion of fiber types within the DIAm, and specific force 273.
Figure 4. Figure 4. (A) An incoming motor neuron action potential is transduced to muscle fiber action potential, intracellular Ca2+ concentration ([Ca2+]i), and force response in a 1:1 ratio. At lower stimulus intensities, the [Ca2+]i and force responses do not summate, but as the frequency of activation increases, both the [Ca2+]i and force responses summate until they fuse. (B) In permeabilized muscle fibers, the relationship between [Ca2+] (pCa) and muscle force exhibits a sigmoidal relation that is shifted left in type I fibers compared with type II fibers 159. (C) The relationship between cat diaphragm muscle (DIAm) motor unit force and phrenic nerve stimulation frequency also displays a sigmoidal curve, which is shifted leftward for slow motor units as compared to fast motor units. Fast fatigue intermediate (FInt) and fast fatigable (FF) motor units display the most rightward shifted force‐frequency response curves 144,425. (D) Single motor unit action potentials or compound summated action potentials in the rat diaphragm muscle (DIAm) were recorded using electromyographic (EMG) electrodes. Single motor unit action potentials were identified by their constant waveform. In this example, the discharge profiles of three single motor units in the rat DIAm were discriminated. (E) Once recruited, the discharge rate of DIAm motor units increases as inspiratory efforts proceed. As inspiratory drive increases, the difference between onset and peak motor unit discharge rate increases, reflected frequency modulation of force generation to accomplish different behaviors 415.
Figure 5. Figure 5. (A) Pre‐ and postsynaptic elements of neuromuscular junctions (NMJs) on rat diaphragm muscle (DIAm) fibers can be visualized by confocal microscopy. Phrenic motor axon and presynaptic terminals were labeled by fluorescence immunostaining using neurofilamin antibody (red). Motor endplates were labeled using fluorescently tagged α‐bungarotoxin (green), which binds to cholinergic receptors. DIAm fiber types were distinguished by immunofluorescence using antibodies specific to different myosin heavy chain (MyHC) isoforms. In this example, immunoreactivity for anti‐MyHC2B was used. The MyHC2B isoform is co‐expressed with MyHC2X in rat DIAm fibers 159 so they are classified as type IIx/IIb. Accordingly, the two NMJs shown in this image are on type IIx/IIb DIAm fibers. (B) Electron micrographic (EM) image of a NMJ on a type IIx/IIb rat DIAm fiber in which it is possible to clearly distinguish the presynaptic terminal containing an active zone, synaptic vesicles, and the motor endplate containing junctional folds. Synaptic vesicles docked near the active zone hypothetically form a readily releasable pool, whereas non‐fused synaptic vesicles form a reserve pool. It is assumed that the availability of synaptic vesicles to fuse with the presynaptic terminal membrane near the active zone depends on the distance from the active zones.
Figure 6. Figure 6. (A) Postsynaptic responses to spontaneous or evoked synaptic vesicle release can be measured electrophysiologically. In this example, the response to the spontaneous exocytosis of ACh was observed as miniature endplate potentials (mEPPs) and more concerted release as evoked endplate potentials (EPPs) were recorded using an intracellular microelectrode in the muscle fiber. The microelectrode (glass micropipette) was inserted into a rat diaphragm muscle (DIAm) fiber near the neuromuscular junction identified by labeling the presynaptic terminal using FM4‐64. (B) Quantal content (QC determined as the ratio of EPP amplitude to mEPP amplitude) was significantly greater in type IIx/IIb DIAm fibers compared with type I and IIa fibers (*P < 0.01) 389. (C) In rat DIAm, the average mEPP amplitude recorded in type IIx/IIb fibers was significantly smaller than that in type I and IIa fibers (*P < 0.05) 389. (D) The frequency of spontaneous mEPPs was comparable among type I, IIa, and IIx/IIb fibers in the rat DIAm 389.
Figure 7. Figure 7. The SNARE protein complex mediates the docking and fusion of synaptic vesicles to the presynaptic terminal membrane. In response to a nerve action potential and depolarization of the presynaptic terminal, this process is initiated by the influx of Ca2+ (represented by the grey circles) via voltage‐gated Ca2+ channels. The elevated intracellular Ca2+ concentration ([Ca2+]i) leads to increased Ca2+ binding to synaptotagmin, which then triggers the signaling cascade responsible for synaptic vesicle fusion to the presynaptic terminal membrane near active zones. The SNARE signaling cascade involves synaptobrevin, mammalian uncoordinated‐18 (Munc18), complexin, and syntaxin working together to fuse the synaptic vesicle membrane to the presynaptic terminal membrane. Ca2+ channels are also tethered close to the synaptic vesicle by Munc13, rab3‐interacting molecules (RIM), and RIM binding protein (RIM‐BP).
Figure 8. Figure 8. (A) The average decline in quantal content (QC) over a 10‐min period of continuous 20‐Hz stimulation at type I or IIa vs type IIx/IIb fibers in the rat diaphragm muscle (DIAm). At both fiber types, there was a rapid early decline in QC (1st 100 s) followed by a slower (late) decline (beyond 300 s). Inset: Shows the immediate decline in QC occurring within the first 0.5 s. (B) The relative change in QC (normalized to the initial QC) is similar across type I or IIa and type IIx/IIb DIAm fibers in both the early and late phases of decline. However, there was a fiber type difference in the immediate decline in QC (<2.5 s; inset), with a greater relative change at type I or IIa fibers compared to that at type IIx/IIb fibers (P < 0.05). (C) The rate of synaptic vesicle replenishment from the reserve pool during repetitive phrenic nerve stimulation (20 or 50 Hz; 0.5 ms pulse duration) was estimated based on the difference between the predicted depletion of the readily‐ releasable pool of synaptic vesicles and the actual QC measurements at DIAm fibers. A higher rate of synaptic vesicle replenishment was observed at type IIx/IIb fibers compared to type I and IIa fibers (*P < 0.05). Figure used with permission from 389.
Figure 9. Figure 9. (A) Confocal imaging of presynaptic terminals at three different rat diaphragm muscle (DIAm) fibers labeled by the uptake of the styryl dye FM4‐64. (B) After loading the terminals with FM4‐64, the dye was washed from the bath and the terminals were destained by repetitive phrenic nerve stimulation at 10 Hz (0.5 ms supramaximal pulses with a 67% duty cycle for a 20‐min period) compared with presynaptic terminals at NMJs on type IIx/IIb fibers. Values are mean ± standard error for single‐exponential fitted curves.
Figure 10. Figure 10. FM4‐64 is applied extracellularly and is taken up into the presynaptic terminal through synaptic vesicle endocytosis. Confocal imaging during this initial process provides information on synaptic vesicle recycling. After loading the presynaptic terminal with FM4‐64, and rinsing the remaining extracellular FM4‐64, synaptic vesicle binding and release can be assessed by the decline in FM4‐64 fluorescence.
Figure 11. Figure 11. (A) Current traces from acetyl choline receptors (AChRs) at motor endplates of frog NMJs: (a) currents measured immediately above the AChR clusters and currents measured a short distance from the junctional folds at weaker (b) and stronger (c) stimulus pulses. Figures reproduced with permissions from 269. (B) The current‐voltage (I‐V) relationship for junctional (open) and extrajunctional (filled) AChRs at motor endplates of frog NMJs recorded using the patch‐clamp technique. The slope of I‐V relationship represents the conductance of the AChR channel. The reversal potential was 0 mV indicating the AChR at frog NMJs is a non‐selective cation channel.
Figure 12. Figure 12. (A) Averaged images from electron microscopy (EM) were used to reconstruct the nicotinic acetylcholine receptor (AChR) at 4.6 A resolution. The top right panel is the intracellular perspective, and the bottom right is extracellular 297. (B) AChRs are more densely clustered, typically at the peak of the junctional folds (red denotes greater density) compared with the troughs. Although this image is of a cultured rat myotube, which does not consistently exhibit junctional folds. Reproduced with copyright permissions from 452. (C) Agrin is released from the presynaptic cleft and binds to muscle‐specific kinase (MuSK) receptors on the muscle fiber. The binding of agrin to MuSK triggers an intracellular cascade that clusters the AChRs. Reproduced with copyright permissions from 308.
Figure 13. Figure 13. (A) Perinatal developmental timeline of the development of phrenic motor neurons and their innervation of muscle fibers in the rat diaphragm muscle (DIAm). (B) Photomicrographs of motor axons and presynaptic terminals labeled using an anti‐body specific for neurofilamin (green) and Schwann cells labeled using an anti‐body for S‐100. The merged image shows the close association of motor axons to Schwann cells. (C) During late embryonic and early postnatal development, DIAm fibers are innervated by more than one phrenic motor neuron (i.e., polyneuronal innervation). Subsequently, polyneuronal innervation disappears via synapse elimination leaving each muscle fiber innervated by only one motor axon.
Figure 14. Figure 14. In the rat diaphragm muscle (DIAm), quantal content (QC) decreases with repeated phrenic nerve stimulation (at 20 or 50 Hz; 0.5 ms pulse duration) in all fiber types (A. type I and IIa; B. type IIx/IIb) 389. A model of the replenishment of the readily releasable pool (RRP) of synaptic vesicles was developed to explain the initial decline of QC and the subsequent leveling of QC. For type I/IIa fibers, the initial decline in QC is steeper than can be explained by the depletion of the RRP, so at least part of this depletion was attributed to a decrease in the probability of synaptic vesicle release. For type IIx/IIb fibers the initial decline in QC was parallel to the depletion of the RRP, which suggests that the depletion is causal. All fiber types exhibit an ability to continuously release synaptic vesicles despite a continual decline in the RRP, therefore the sustained release is due to the repletion of synaptic vesicles through synaptic vesicle recycling. The probability of release and repletion of the RRP is difficult to directly measure so these remain suggested mechanisms, hence the question mark in the figure. The probability of release remains relatively unchanged at low compared to high frequencies for type I and IIa fibers. In contrast, higher frequencies substantially decrease the probability of release at type IIx/IIb DIAm fibers.
Figure 15. Figure 15. Neuromuscular transmission failure (NMTF) can occur due to failures at both the presynaptic and postsynaptic components of the neuromuscular junction (NMJ). At the presynaptic component, NMTF can be subdivided into branch point failure and a failure to release synaptic vesicles, which can be caused by either a decrease in the probability of release or depletion of the synaptic vesicle pools.
Figure 16. Figure 16. (A) One approach to test neuromuscular transmission failure (NMTF) is to repeatedly stimulate motor axons and compared the evoked forces to those evoked by intermittent direct muscle stimulation. NMTF is quantified as the difference between the amplitude of the forces evoked by direct muscle vs nerve stimulation. In the rat diaphragm muscle (DIAm), the extent of NMTF is dependent on the frequency of phrenic nerve stimulation such that at lower frequencies (B. 10 Hz) there is less divergence in the forces evoked by direct muscle versus nerve stimulation (i.e., less NMTF) than at higher frequencies (C. 75 Hz) 213.
Figure 17. Figure 17. Neurotrophin 4 (NT‐4) and brain‐derived neurotrophic factor (BDNF) are predominantly produced and released by motor neurons, although there is some evidence suggesting a myogenic pathway for these neurotrophins. Both NT‐4 and BDNF bind to a high affinity tropomyosin kinase B (TrkB) receptor located both pre‐ and postsynaptically. Some evidence suggests that TrkB and BDNF in the bound state are endocytosed and transported retrogradely via the axon to provide signaling to the soma. Republished, with permission, from Mantilla CB and Sieck GC, 2003 274.


Figure 1. For a given level of glutamatergic input current (Isyn), the change in membrane potential (dVm/dt) will be greater for smaller motor neurons due to their lower membrane capacitance (size; Cm) and higher input resistance (Rin) compared to larger motor neurons. Thus, smaller motor neurons will reach the threshold for action potential generation sooner (i.e., earlier recruitment) than larger motor neurons. Smaller motor neurons also have smaller axons with slower action potential propagation velocities compared to larger motor neurons. These relationships constitute the Henneman's size principle for motor unit recruitment.


Figure 2. (A) Imaging of the phrenic motor neuron pool from rats acquired by confocal microscopy after labeling with tetramethylrhodamine‐dextran (nerve‐dip) or cholera toxin B (CTB) injected into the intrapleural space. Reused, with permission, from Mantilla CB, et al., 2009/ELSEVIER 279. (B) The distribution of phrenic motor neuron somal surface areas divided into tertiles. (C) Smaller motor neurons comprise slow (S; type I muscle fibers) and fast, fatigue‐resistant (FR; type IIa muscle fibers) motor units, whereas larger motor neurons comprise fast fatigue intermediate (FInt; type IIx muscle fibers) and fast fatigable (FF; type IIb muscle fibers). (D) In the rat diaphragm muscle (DIAm), a model predicting motor unit recruitment during different motor behaviors was developed based on (i) a recruitment order dependent on motor neuron size (S first FF last), (ii) the forces generated by each motor unit type, and (iii) the relative proportion of each motor unit type. The model predictions were compared to the transdiaphragmatic pressure (Pdi) or force generated by the DIAm 273. Based on this model, the lower Pdi generated during quiet breathing (eupnea) and hypercapnia/hypoxia stimulated breathing required the recruitment of only fatigue‐resistant S and FR motor units. In contrast, with more forceful (higher Pdi) DIAm efforts (e.g., coughing/sneezing and voiding) require recruitment of the entire phrenic motor neuron pool, including more fatigable FInt and FF motor units.


Figure 3. (A) Fiber‐type classification in the rat diaphragm muscle (DIAm) is based on immunoreactivity to primary antibodies for myosin heavy chain (MyHC) isoforms (pseudo‐colored in this example). Reused, with permission, from Mantilla CB, et al., 2010/ELSEVIER 273. (B) Composite table based on results from a number of studies displaying mean ± SD of muscle fiber cross‐sectional area, the proportion of fiber types within the DIAm, and specific force 273.


Figure 4. (A) An incoming motor neuron action potential is transduced to muscle fiber action potential, intracellular Ca2+ concentration ([Ca2+]i), and force response in a 1:1 ratio. At lower stimulus intensities, the [Ca2+]i and force responses do not summate, but as the frequency of activation increases, both the [Ca2+]i and force responses summate until they fuse. (B) In permeabilized muscle fibers, the relationship between [Ca2+] (pCa) and muscle force exhibits a sigmoidal relation that is shifted left in type I fibers compared with type II fibers 159. (C) The relationship between cat diaphragm muscle (DIAm) motor unit force and phrenic nerve stimulation frequency also displays a sigmoidal curve, which is shifted leftward for slow motor units as compared to fast motor units. Fast fatigue intermediate (FInt) and fast fatigable (FF) motor units display the most rightward shifted force‐frequency response curves 144,425. (D) Single motor unit action potentials or compound summated action potentials in the rat diaphragm muscle (DIAm) were recorded using electromyographic (EMG) electrodes. Single motor unit action potentials were identified by their constant waveform. In this example, the discharge profiles of three single motor units in the rat DIAm were discriminated. (E) Once recruited, the discharge rate of DIAm motor units increases as inspiratory efforts proceed. As inspiratory drive increases, the difference between onset and peak motor unit discharge rate increases, reflected frequency modulation of force generation to accomplish different behaviors 415.


Figure 5. (A) Pre‐ and postsynaptic elements of neuromuscular junctions (NMJs) on rat diaphragm muscle (DIAm) fibers can be visualized by confocal microscopy. Phrenic motor axon and presynaptic terminals were labeled by fluorescence immunostaining using neurofilamin antibody (red). Motor endplates were labeled using fluorescently tagged α‐bungarotoxin (green), which binds to cholinergic receptors. DIAm fiber types were distinguished by immunofluorescence using antibodies specific to different myosin heavy chain (MyHC) isoforms. In this example, immunoreactivity for anti‐MyHC2B was used. The MyHC2B isoform is co‐expressed with MyHC2X in rat DIAm fibers 159 so they are classified as type IIx/IIb. Accordingly, the two NMJs shown in this image are on type IIx/IIb DIAm fibers. (B) Electron micrographic (EM) image of a NMJ on a type IIx/IIb rat DIAm fiber in which it is possible to clearly distinguish the presynaptic terminal containing an active zone, synaptic vesicles, and the motor endplate containing junctional folds. Synaptic vesicles docked near the active zone hypothetically form a readily releasable pool, whereas non‐fused synaptic vesicles form a reserve pool. It is assumed that the availability of synaptic vesicles to fuse with the presynaptic terminal membrane near the active zone depends on the distance from the active zones.


Figure 6. (A) Postsynaptic responses to spontaneous or evoked synaptic vesicle release can be measured electrophysiologically. In this example, the response to the spontaneous exocytosis of ACh was observed as miniature endplate potentials (mEPPs) and more concerted release as evoked endplate potentials (EPPs) were recorded using an intracellular microelectrode in the muscle fiber. The microelectrode (glass micropipette) was inserted into a rat diaphragm muscle (DIAm) fiber near the neuromuscular junction identified by labeling the presynaptic terminal using FM4‐64. (B) Quantal content (QC determined as the ratio of EPP amplitude to mEPP amplitude) was significantly greater in type IIx/IIb DIAm fibers compared with type I and IIa fibers (*P < 0.01) 389. (C) In rat DIAm, the average mEPP amplitude recorded in type IIx/IIb fibers was significantly smaller than that in type I and IIa fibers (*P < 0.05) 389. (D) The frequency of spontaneous mEPPs was comparable among type I, IIa, and IIx/IIb fibers in the rat DIAm 389.


Figure 7. The SNARE protein complex mediates the docking and fusion of synaptic vesicles to the presynaptic terminal membrane. In response to a nerve action potential and depolarization of the presynaptic terminal, this process is initiated by the influx of Ca2+ (represented by the grey circles) via voltage‐gated Ca2+ channels. The elevated intracellular Ca2+ concentration ([Ca2+]i) leads to increased Ca2+ binding to synaptotagmin, which then triggers the signaling cascade responsible for synaptic vesicle fusion to the presynaptic terminal membrane near active zones. The SNARE signaling cascade involves synaptobrevin, mammalian uncoordinated‐18 (Munc18), complexin, and syntaxin working together to fuse the synaptic vesicle membrane to the presynaptic terminal membrane. Ca2+ channels are also tethered close to the synaptic vesicle by Munc13, rab3‐interacting molecules (RIM), and RIM binding protein (RIM‐BP).


Figure 8. (A) The average decline in quantal content (QC) over a 10‐min period of continuous 20‐Hz stimulation at type I or IIa vs type IIx/IIb fibers in the rat diaphragm muscle (DIAm). At both fiber types, there was a rapid early decline in QC (1st 100 s) followed by a slower (late) decline (beyond 300 s). Inset: Shows the immediate decline in QC occurring within the first 0.5 s. (B) The relative change in QC (normalized to the initial QC) is similar across type I or IIa and type IIx/IIb DIAm fibers in both the early and late phases of decline. However, there was a fiber type difference in the immediate decline in QC (<2.5 s; inset), with a greater relative change at type I or IIa fibers compared to that at type IIx/IIb fibers (P < 0.05). (C) The rate of synaptic vesicle replenishment from the reserve pool during repetitive phrenic nerve stimulation (20 or 50 Hz; 0.5 ms pulse duration) was estimated based on the difference between the predicted depletion of the readily‐ releasable pool of synaptic vesicles and the actual QC measurements at DIAm fibers. A higher rate of synaptic vesicle replenishment was observed at type IIx/IIb fibers compared to type I and IIa fibers (*P < 0.05). Figure used with permission from 389.


Figure 9. (A) Confocal imaging of presynaptic terminals at three different rat diaphragm muscle (DIAm) fibers labeled by the uptake of the styryl dye FM4‐64. (B) After loading the terminals with FM4‐64, the dye was washed from the bath and the terminals were destained by repetitive phrenic nerve stimulation at 10 Hz (0.5 ms supramaximal pulses with a 67% duty cycle for a 20‐min period) compared with presynaptic terminals at NMJs on type IIx/IIb fibers. Values are mean ± standard error for single‐exponential fitted curves.


Figure 10. FM4‐64 is applied extracellularly and is taken up into the presynaptic terminal through synaptic vesicle endocytosis. Confocal imaging during this initial process provides information on synaptic vesicle recycling. After loading the presynaptic terminal with FM4‐64, and rinsing the remaining extracellular FM4‐64, synaptic vesicle binding and release can be assessed by the decline in FM4‐64 fluorescence.


Figure 11. (A) Current traces from acetyl choline receptors (AChRs) at motor endplates of frog NMJs: (a) currents measured immediately above the AChR clusters and currents measured a short distance from the junctional folds at weaker (b) and stronger (c) stimulus pulses. Figures reproduced with permissions from 269. (B) The current‐voltage (I‐V) relationship for junctional (open) and extrajunctional (filled) AChRs at motor endplates of frog NMJs recorded using the patch‐clamp technique. The slope of I‐V relationship represents the conductance of the AChR channel. The reversal potential was 0 mV indicating the AChR at frog NMJs is a non‐selective cation channel.


Figure 12. (A) Averaged images from electron microscopy (EM) were used to reconstruct the nicotinic acetylcholine receptor (AChR) at 4.6 A resolution. The top right panel is the intracellular perspective, and the bottom right is extracellular 297. (B) AChRs are more densely clustered, typically at the peak of the junctional folds (red denotes greater density) compared with the troughs. Although this image is of a cultured rat myotube, which does not consistently exhibit junctional folds. Reproduced with copyright permissions from 452. (C) Agrin is released from the presynaptic cleft and binds to muscle‐specific kinase (MuSK) receptors on the muscle fiber. The binding of agrin to MuSK triggers an intracellular cascade that clusters the AChRs. Reproduced with copyright permissions from 308.


Figure 13. (A) Perinatal developmental timeline of the development of phrenic motor neurons and their innervation of muscle fibers in the rat diaphragm muscle (DIAm). (B) Photomicrographs of motor axons and presynaptic terminals labeled using an anti‐body specific for neurofilamin (green) and Schwann cells labeled using an anti‐body for S‐100. The merged image shows the close association of motor axons to Schwann cells. (C) During late embryonic and early postnatal development, DIAm fibers are innervated by more than one phrenic motor neuron (i.e., polyneuronal innervation). Subsequently, polyneuronal innervation disappears via synapse elimination leaving each muscle fiber innervated by only one motor axon.


Figure 14. In the rat diaphragm muscle (DIAm), quantal content (QC) decreases with repeated phrenic nerve stimulation (at 20 or 50 Hz; 0.5 ms pulse duration) in all fiber types (A. type I and IIa; B. type IIx/IIb) 389. A model of the replenishment of the readily releasable pool (RRP) of synaptic vesicles was developed to explain the initial decline of QC and the subsequent leveling of QC. For type I/IIa fibers, the initial decline in QC is steeper than can be explained by the depletion of the RRP, so at least part of this depletion was attributed to a decrease in the probability of synaptic vesicle release. For type IIx/IIb fibers the initial decline in QC was parallel to the depletion of the RRP, which suggests that the depletion is causal. All fiber types exhibit an ability to continuously release synaptic vesicles despite a continual decline in the RRP, therefore the sustained release is due to the repletion of synaptic vesicles through synaptic vesicle recycling. The probability of release and repletion of the RRP is difficult to directly measure so these remain suggested mechanisms, hence the question mark in the figure. The probability of release remains relatively unchanged at low compared to high frequencies for type I and IIa fibers. In contrast, higher frequencies substantially decrease the probability of release at type IIx/IIb DIAm fibers.


Figure 15. Neuromuscular transmission failure (NMTF) can occur due to failures at both the presynaptic and postsynaptic components of the neuromuscular junction (NMJ). At the presynaptic component, NMTF can be subdivided into branch point failure and a failure to release synaptic vesicles, which can be caused by either a decrease in the probability of release or depletion of the synaptic vesicle pools.


Figure 16. (A) One approach to test neuromuscular transmission failure (NMTF) is to repeatedly stimulate motor axons and compared the evoked forces to those evoked by intermittent direct muscle stimulation. NMTF is quantified as the difference between the amplitude of the forces evoked by direct muscle vs nerve stimulation. In the rat diaphragm muscle (DIAm), the extent of NMTF is dependent on the frequency of phrenic nerve stimulation such that at lower frequencies (B. 10 Hz) there is less divergence in the forces evoked by direct muscle versus nerve stimulation (i.e., less NMTF) than at higher frequencies (C. 75 Hz) 213.


Figure 17. Neurotrophin 4 (NT‐4) and brain‐derived neurotrophic factor (BDNF) are predominantly produced and released by motor neurons, although there is some evidence suggesting a myogenic pathway for these neurotrophins. Both NT‐4 and BDNF bind to a high affinity tropomyosin kinase B (TrkB) receptor located both pre‐ and postsynaptically. Some evidence suggests that TrkB and BDNF in the bound state are endocytosed and transported retrogradely via the axon to provide signaling to the soma. Republished, with permission, from Mantilla CB and Sieck GC, 2003 274.
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Leah A. Davis, Matthew J. Fogarty, Alyssa Brown, Gary C. Sieck. Structure and Function of the Mammalian Neuromuscular Junction. Compr Physiol 2022, 12: 1-36. doi: 10.1002/cphy.c210022