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AChR topography and distribution do not mature at denervated neonatal neuromuscular junctions. At P17, 10 d after the sternomastoid muscle is denervated, the postsynaptic AChR distribution is oval, and well defined gutters are not present. Both of these features are seen commonly in junctions of much younger ages. This work adds to the extensive literature on neuromuscular junction structure by providing a topographical representation of location of AChRs. Additionally, this is the first optical technique capable of generating a high-resolution topography of the junctional folding pattern; it requires no sectioning or nerve removal procedure as is needed in electron microscopical approaches.

We found that during the first few postnatal weeks the postsynaptic membrane at individual neuromuscular junctions is a mosaic of two different regions. Some regions of the membrane are less reflective and have less organized folding, whereas other areas show folds and are associated with newly forming gutters.

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The transition from polyneuronal to single innervation is associated with a disappearance of AChRs at the underlying postsynaptic sites Balice-Gordon and Lichtman, ; Gan and Lichtman, It is possible that the sites that showed reduced AChR reflection are associated with synapses that are eliminated. This suggests that eliminated synapses generally may not be associated with receptor-rich postsynaptic membranes having primary synaptic clefts and secondary folds. It is not clear, however, whether the absence of folds at sites losing AChRs is because such sites never differentiated folds or, alternatively, because these sites have undergone a process of dedifferentiation.

This work provides insight into the mechanism that generates the patterns of branches within a neuromuscular junction and the arrangement of folds within each branch. We saw that the nascent gutters of the future primary synaptic clefts fan out in a radial pattern in the oval plaque of AChRs see, for example, Figs.

The entry site also is associated with postsynaptic remodeling, because virtually all junctions became asymmetric; the outlines of the original oval AChR plaque remained evident at those edges of the junction that are not near the site of nerve entry, whereas the loss of AChRs disrupted the oval outline at the entry zone. Because the multiple inputs always approach the plaque from the same side Balice-Gordon and Lichtman, and probably innervate the muscle shortly after entering the junction, the loss of all but one axon will lead inevitably to the disappearance of some nerve terminal sites near the entry zone.

In addition, myelination of the preterminal axon can extend gradually into the entry zone of the neuromuscular junction. Myelination also causes a loss of AChRs at sites in which the overlying nerve becomes ensheathed [ Balice-Gordon and Lichtman , their Fig. Thus the nerves play a role in determining the branching pattern in the pretzel-shaped neuromuscular junction. The muscle, however, is also apparently responsible for dictating some aspects of synaptic organization. We observed that mammalian junctions often have folds that run transverse to the long axis of the muscle fiber irrespective of the orientation of the gutters see Fig.

Thus when junctional gutters were running in the long axis of the muscle fiber, the folds were transverse to the gutters, but when the gutters were running transverse to the long axis, the folds often were parallel to the gutter orientation. Previous scanning electron microscopical studies based on smaller sample sizes had noted that folds often were transverse to gutters Ogata and Yamasaki, ; Desaki and Uehara, , which may be related to the fact that more gutters run along the long axis of the muscle fiber than in the transverse direction see Fig. Similarly, in frog neuromuscular junctions the folds are also generally transverse to the long axis of the primary synaptic clefts, but these gutters also predominantly run parallel to the long axis of the fibers Shotton et al.

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Thus, in contrast to the situation for the organization of the branches of the primary synaptic cleft, the pattern of junctional folds seems to be imposed at least partially by the orientation of the muscle fiber. This ability of the muscle to determine the orientation of the junctional folds has motivated us to consider an explanation for the origin of junctional folds based on the forces exerted on the postsynaptic membrane as a consequence of the growth of muscle fibers and adhesion to the nerve.

Analogous arguments have related tension forces that act in the developing brain to the origin of sulci and gyri and other structural features of the CNS Van Essen, The hypothesis we came up with also provides a conceptual framework for thinking about the origin of three other topographical features observed in this study: the concavity of the junctional gutters, the concavity of the early spoon-shaped junctional plaque, and the reasoning for active zones that overlie postsynaptic folds. We consider the consequences for the topography of the synapse that result from acknowledging that sites of synaptic contact are tightly adhesive for the pre- and postsynaptic membranes.

Evidence for this strong adhesion comes from the requirement of harsh acid or proteolytic treatments to strip nerve terminals from muscle fibers Kuffler and Yoshikami, ; Fahim et al. We also consider the fact that the elongation and widening of muscle fibers during normal growth are associated with intercalary membrane addition throughout the muscle fiber, as seen in the intercalary enlargement of the AChR distribution as muscle fibers grow Balice-Gordon and Lichtman, ; Balice-Gordon et al.

The intercalary membrane addition in muscle fibers thus may cause the established sites of adhesion with the nerve terminal via the intervening basal lamina to be pushed apart by new membrane insertion in the growing muscle fiber. If the connective tissue between the nerve and muscle is relatively inelastic, the adhesion between nerve terminals and muscle fibers will exert forces on the muscle fiber membrane associated with muscle growth.

The concave shape of the AChR plaque in neonatal animals thus may be a consequence of the inability of the nerve to enlarge as fast as the expansion of the muscle fiber membrane. Disproportionate growth between muscle and nerve also may be the explanation for the subsequent sinking of the synaptic gutters as the muscle continues to add membrane at sites near contact with less quickly growing nerve terminal branches Fig. Hypothesis for the role of adhesion in generating three-dimensional topography of the neuromuscular junction.

Shown are three stages in the development of the mammalian neuromuscular junction. Left , When nerve first contacts the muscle, sites of adhesion are established between the nerve terminal plasmalemma and the membrane of the myofiber via molecules that extend into the basal lamina red and blue lines. Middle , as the muscle fiber grows to keep pace with the enlargement of the body, new membrane green is inserted in the membrane.

This insertion causes an intercalary expansion of the postsynaptic site Balice-Gordon and Lichtman, ; Balice-Gordon et al. As a result of this postsynaptic growth, tension is exerted on the sites of adhesion, causing the muscle fiber to curl around the less elastic nerve terminal. Thus the adhesive struts go from a parallel to a radial orientation at points a , b , and c.

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As new membrane is added, new adhesive interconnections are established red lines. Right , As the muscle fiber continues to grow preferentially in the orientation of its long axis, more new membrane is inserted. It is likely that presynaptic sites undergoing exocytosis and endocytosis cannot maintain adhesive interconnections; thus the underlying postsynaptic membrane can infold at presynaptic active zones black triangles. If preferential muscle fiber growth is not matched by an equivalently rapid growth of the nerve terminal, then the nerve will prevent the elongation of the postsynaptic territory attached to it.

In the presence of this restraining force any newly inserted muscle fiber membrane would have to fold to accommodate the constraints imposed by attachment to the nerve terminal. One location in which such infolding might occur is at sites in which there are few adhesive connections between the nerve and the underlying muscle.

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Adhesive connections are thought to occur around, but not at, release sites of central synapses Uchida et al. Similarly, at the neuromuscular junction there is evidence of adhesive struts adjacent to active zones but an absence of adhesion at the release sites in which the basal lamina pulls away slightly from the nerve terminal [see, for example, Heuser , his Fig.

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Muscle fiber membrane expansion thus would be selectively permissible at those sites, explaining why active zones overlie postsynaptic folds. In addition, if in early postnatal life muscle growth happens to be preferential in the long axis of the fiber, then the preferred orientation of folds would be transverse to the long axis. This conceptual framework also provides a potential explanation for the loss of folds seen in denervated adult muscles although AChRs are maintained Loring and Salpeter, and for the complete arrest in fold and gutter formation in development that follows the denervation described here.

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In adult denervated muscles the disappearance of folds may be accounted for by the membrane loss associated with muscle fiber atrophy. Consistent with this is that there is a 1—2 week lag before folds disappear and a similar lag before atrophy is severe. On the other hand, the absence of tension forces associated with nerve in neonatal denervation could be the reason that fold and cleft formation ceases after denervation in neonates. The fact that the depths of folds vary between muscle types and species also may be explained by differences in the growth potential or elasticity of nerve terminals.

For example, human neuromuscular junctions are typically smaller than mouse junctions, although often they are located on muscle fibers that are much larger. Human junctions, however, do have much longer junctional infoldings and deeper gutters Engel and Santa, Thus the relative lack of nerve elongation in human muscle may explain why the folds and clefts are so deep and complex but the junctions are so small when compared with mouse.

Although such mechanical explanations do not explain the functional significance of folds, they may be helpful in considering a number of questions related to the alignment of folds with active zones and the reasons why certain molecular perturbations cause changes in junctional folding see, for example, Deconinck et al.

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Previous Next. Maria Julia Marques. Louis, Missouri Abstract Although there has been progress in understanding the initial steps in the formation of synapses, less is known about their subsequent maturation Sanes and Lichtman, View this table: View inline View popup. Table 1. J Neurosci 10 : — Balice-Gordon RJ , Lichtman JW In vivo observations of pre- and postsynaptic changes during the transition from multiple to single innervation at developing neuromuscular junctions.

J Neurosci 13 : — Balice-Gordon RJ , Breedlove SM , Bernstein S , Lichtman JW Neuromuscular junctions shrink and expand as muscle fiber size is manipulated: in vivo observations in the androgen-sensitive bulbocavernosus muscle of mice. Neuron 11 : — J Physiol Lond : — Science : — J Cell Biol : — Desaki J , Uehara Y Formation and maturation of subneural apparatuses at neuromuscular junctions in postnatal rats: a scanning and transmission electron microscopical study.

Dev Biol : — Engel AG , Santa T Histometric analysis of the ultrastructure of the neuromuscular junction in myasthenia gravis and in the myasthenic syndrome. Ann NY Acad Sci : 46 — J Neurocytol 12 : 13 — Neuron 3 : — Heuser J 3-D visualization of membrane and cytoplasmic specializations at the frog neuromuscular junction.

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