Axonal atrophy: The retraction reaction

364

Axonal atrophy: the retraction reaction Michael Bernstein* and Jeff W Lichtmanf

Recent studies indicate that morphological alterations of axon

branches that are removed during normal development are

similar to those that occur following ablation of postsynaptic cells in adult animals. In both situations, axons retract (rather

than degenerate), the calibers of withdrawing axon branches

are markedly reduced, and spherical swellings near (or at) the axon terminations appear. The similarity between naturally

occurring and target-deprived axon withdrawal suggests that

both developing and adult axons withdraw from target cells that no longer provide support.

Addresses Department of Anatomy and Neurobiology, Box 8108, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA *e-mail: [email protected] te-mail: [email protected]

Current Opinion in Neurobiology 1999, 9:364-370

http:/lbiomednet.com/elecref/0959438800900364

0 Elsevier Science Ltd ISSN 0959-4388

Abbreviations Dil 1 ,l’-dioctadecyl-3,3,3’,3’-tetramethylindocarbocyanine

perchlorate DiO 3,Xdioctadecyloxacarbocyanine perchlorate NGF nerve growth factor

Introduction Given the overwhelming number of synapses in the brain, it is not surprising that developmental neurobiology has focussed more on mechanisms that establish connections than on mechanisms that remove them. There is little doubt, however, that the generation of the nervous system requires some degree of synaptic reorganization, Indeed, throughout the developing nervous system there are exam- ples of the dismantling of axon pathways and synapses [1,2]. Even though loss of synaptic connections is quanti- tatively less impressive than concurrent synaptogenesis during development, there are good reasons to believe that synaptic removal plays a pivotal role in experience-mediated modifications. For example, synapse loss is responsible for the permanent defect in vision following monocular deprivation in early postnatal life [3,4]. It is possible that experience-based synaptic removal is one of the primary means by which mammalian, and especially human, nervous systems differentiate themselves from other animals and other individuals within their species.

The mechanism of synapse elimination is being studied in several parts of the nervous system, but, as yet, there is no consensus. It is likely that in all cases, synapse loss has both a functional and structural component. In addition, in developing autonomic ganglia, muscle, cerebellum, and the visual system, synapse elimination seems more directed at

reducing the number of different axons that innervate a target cell than with reducing the total number of synapses. Indeed, in autonomic ganglia, the loss of axonal input is correlated with an increase in the number of synapses, as the remaining axon establishes new connections that more than compensate for the synapses that disappear as other axons withdraw [5].

This apparent disconnection between the regulation of the number of synapses and number of innervating axons suggests that these properties of synaptic circuits are controlled independently. How and why axons withdraw, however, has received scant attention and therefore even basic questions concerning axon withdrawal remain unan- swered. For example, it is not known why an axon that has lost all its synaptic connections with a postsynaptic cell does not respond by sprouting in an attempt to find new targets. Axons do respond when damaged by sprouting, but this response apparently is not a feature of the axon’s behavior during naturally occurring synapse elimination (see below). It is also not known whether removal of axon branches is the consequence or, alternatively, related to the cause of synapse elimination. Our aim in this review is to highlight changes that axonal branches undergo during synaptic remodeling and explore the hypothesis that axonal atrophy is a fundamental part of the retraction reaction - that is, the axonal response to target cells that have ceased providing support.

Axonal atrophy at the neuromuscular junction Naturally occurring synapse elimination in mammalian (and other terrestrial vertebrate) skeletal muscle reduces the number of axons innervating each neuromuscular junction during the first few postnatal weeks. From a physiological standpoint, it has long been appreciated that this loss is linked to a parallel change in axonal conver- gence: each motor axon generates a smaller percentage of total muscle tension at the end of the period of synapse elimination than it did at the beginning [6]. Thus, it appears that in most muscles, axons are synaptically con- nected with more muscle fibers initially than they will ultimately innervate and, therefore, that synapse elimination removes axonal branches.

Anatomical analysis of neuromuscular junctions undergoing synapse elimination provides insight into what happens to branches that disconnect from target cells. In early postnatal life, neuromuscular junctions that were previously multiply innervated can be observed with one intact axon and one axon that is in retreat. These withdrawing axons show a characteristic morphology, termed ‘retraction bulbs’ by Riley [7]. These structures are striking and unmistak- able: very thin axon branches that terminate in a large and often nearly spherical protuberance.

Axonal atrophy: the retraction reaction Bernstein and Lichtman 365

Study of the details of neuromuscular synapse elimination indicates that the stereotyped retraction of an axon from a muscle fiber is the final step in a protracted competition between different axons that converge temporally at the same junction. At birth, the synaptic connections of the competing axons are intermingled and have similarly sized territories and efficacies. However, over the following several weeks, the areas occupied [8] and relative synaptic strengths [9’] become skewed in favor of one input. The reduction in synaptic strength associated with synapse elimination had both a presynaptic component (reduction in the number of released quanta or quanta1 content) and a postsynaptic component (reduction in the efficacy of each quantum). It is likely that the loss of quanta1 content was the physiological correlate of the withdrawal of synaptic branches and reduction of synaptic area.

Structural details of this process have been examined by lipophilic dye (i.e. DiI or DiO) labeling of individual axons in developing junctions [ 10’1. The main conclusion of the labeling study was that the intermingled axonal territories of competing axons segregate before axonal withdrawal by the losing axon. Branches that were most likely to be removed imminently (i.e. those closest to the territory occupied by the competing axon) were thinner than branches located at a greater distance from the competitor, and these soon to be lost branches typically possessed bulb-like endings that were reminiscent of retraction bulbs (see Figure 1). This similarity suggests that axon branch withdrawal during synaptic segregation is mediated by the same mechanism as the more proximal axonal branch withdrawal that completely removes an axon from a junction.

The signals that instigate the atrophy and withdrawal of axonal branches may come from the muscle fiber. This idea is supported by evidence that postsynaptic site dismantling precedes axon withdrawal [8,11,12], implying that synapse elimination takes place when the postsynaptic cell withholds agents necessary for axon survival or secretes agents that are inimical for axon survival. Studies of the axonal reaction to removal of postsynaptic targets have tested directly whether alterations in the target cell can influence axon survival. Muscle fibers can be killed without directly damaging nerve terminals by cutting them at some distance from the central endplate zone. /n situ imaging of mouse neuromuscular junctions shows that nerve terminals respond to muscle fiber damage by retracting some of their branches [13]. Interestingly, in amphibians, the retraction process is much more protracted, taking months rather than days [ 141.

Recent experiments using transgenic mice expressing green fluorescent protein (GFP) in motor axons have allowed further analysis of nerve terminal branches after muscle death (ML Bernstein, G Feng, JR Sanes, JW Lichtman, unpublished data). When a single muscle fiber is killed (with care taken not to damage any motor axons), retraction of terminal axon branches begins

3-4 days later. The retracting branches often possess expanded regions that look like retraction bulbs. By 4 days, the caliber of the preterminal axon branch to the damaged fiber is dramatically smaller (Figure 2). When a new postsynaptic muscle fiber regenerates from the remaining satellite cells, the atrophic nerve branch innervates the new muscle fiber, new terminal branches of the axon are established and the caliber of the preterminal axon returns to normal. Blocking protein synthesis in muscle fibers, by intracellular injection of protein synthesis inhibitors, also results in loss of terminal branches and atrophy of the preterminal axon ([15]; QT Nguyen, H Santo Neto, JW Lichtman, unpublished data). In summary, these experiments support the hypothesis that muscle fibers provide an ongoing signal that both maintains nerve terminals and sustains the caliber of axonal branches, and that loss of this signal results in atrophy and withdrawal.

Climbing fiber atrophy in the cerebellum The unique organization of climbing fiber innervation of Purkinje cells in the cerebellum also provides a simple system for examining interactions between pre- and postsynaptic cells. Much the same as in muscle, several axons converge temporarily on a single Purkinje cell at birth. The innervation is initially concentrated on the Purkinje cell soma, but over a period of several weeks, the axons of the climbing fibers grow out along the dendritic branches of the Purkinje cell [16]. Coincident with this growth, all but one climbing fiber axon and its synapses are eliminated [ 171. This loss results in the adult pattern of innervation whereby each Purkinje cell is strongly, and often exclusively, innervated by a single climbing fiber, with branches that spread out over the Purkinje cell dendrites [ 16,171.

Although the inaccessibility of the cerebellar cortex for vital imaging has thus far precluded detailed examination of the withdrawal of climbing fibers during normal development, it has been possible to examine the effects of Purkinje cell death on climbing fibers. Experiments causing rapid degeneration of Purkinje cells, either by kainic acid or propidium iodide injection, have demonstrated dramatic climbing fiber alterations starting within a few days of the lesion ([18]; for reviews, see [ 19-211). These changes include both retraction of the most distal branches of the climbing fiber arbor and atrophy of the preterminal axon trunk. One month after the lesion, the most distal branches are almost completely gone, many proximal branches are also lost, and all remaining branches have further decreased in caliber. An additional finding associated with climbing fiber retraction is spherical axon swellings [18]. As illustrat- ed in Figure 2, the constellation of changes seen in climbing fibers deprived of their targets is similar to those seen in motor axons following muscle fiber death. Surprisingly, in the absence of its postsynaptic target, the climbing fiber persists for up to six months: albeit in an atrophic state. This has raised the possibility that distal and proximal compartments of the axon respond differently to target loss [18,19]. Mutant mice with cerebellar defects

366 Signalling mechanisms

Figure 1

r Morphological changes in axon branches that are removed during synapse elimination at the neuromuscular junction in mouse

(a) W

Current Opmon in Neurobiology

Diagram illustrating the morphological changes in axon branches that are removed during synapse elimination at the neuromuscular junction. (a) Two axons innervating a single junction in the mouse sternomastoid muscle approximately one week after birth. The axons innervate the same plaque of acetylcholine receptors (light gray) and their branches are intermingled. (b) Within several days, the branches of each axon nearest the main area occupied by the other axon become atrophic and develop bulbs at their tips. In parallel with the axon changes, the underlying receptors gradually disappear. (c) The retraction of the branches results in the axons occupying non- overlapping areas. (d) Shortly thereafter, one axon withdraws completely from the junction, atrophies toward the parent axon and develops a bulb-like shape at its terminus.

associated with Purkinje cell degeneration also have atrophic climbing fibers with retracted distal branches [ZZ], demonstrating that the climbing fiber changes are not a result of either the kainic acid or propidium iodide injections into the cerebellum.

Axonal atrophy in other parts of the nervous system In several other parts of the brain, evidence suggests that axons also undergo alterations when they are deprived of their targets. Retraction of axon terminal branches of dorsal column neurons has been observed when their postsynaptic targets in the rostra1 thalamus were killed by kainate injections [23,24]. Within eight days, the density of axon projections in the thalamus began to decrease. The decrease in projection density was shown to be the result of terminal branch loss and was not attributable to cell death or degeneration of the main axon branches. Slightly preceding the withdrawal of axon terminals, axon swellings termed ‘spher- oids’ appeared. Kainate injections cause changes that are inferred to be axon retraction in several other regions as well. For example, kainate lesions in the lateral geniculate of the thalamus lead to retraction of retinal ganglion cell

axons and the formation of axonal swellings [ZS]. In sum, it appears that in many and perhaps all systems, axons depend on their postsynaptic targets for the maintenance of their arbors. Because the terminal axonal swelling can be con- fused for growth cones (compare [26] with [24]), it is possible that there are other situations in which axon retraction takes place but has been misinterpreted.

Mechanisms regulating morphological changes in axons Ultrastructural changes There seem to be three morphological alterations of axons associated with naturally occurring developmental synapse elimination and experimental target deprivation: atrophy, branch retraction, and the appearance of axonal swellings. Like so many other aspects of neuronal behavior, Cajal first described these phenomena in many parts of the experimentally lesioned nervous system [27]. He used terms such as retraction clubs, balls and buds to describe the changes that take place in proximal axons after distal damage or damage to their targets. The ultrastructural fea- tures of withdrawing axons have been studied at both the developing neuromuscular junction and target-deprived


Figure 2

Illustration showing axon changes following target cell death in muscle and cerebellum in the mouse. (a) At each adult neuromuscular junction (left), one motor axon elaborates a terminal arborization (black) that coincides with the postsynaptic acetylcholine receptor pattern (gray). Four days after selectively killing the muscle fiber (right), the axon branches have withdrawn from some previously occupied sites, the axon is thin and axonal swellings appear. (b) A climbing fiber (black) singly innervates a Purkinje cell (gray) in the mature cerebellum (left). Before damage, the climbing fiber contacts the dendrites of the Purkinje cell. After selective killing of the Purkinje cell (right), the caliber of the climbing fiber axon decreases, terminal branches are lost, and spherical swellings appear in the climbing fiber axon.

Axon changes following target cell death in muscle and cerebellum

(a) Withdrawal and atrophy at the neuromuscular junction

(b) Withdrawal and atrophy of the climbing fiber

Current Opinion in Neurobdogy

dorsal column nucleus axonal projections. Neuromuscular retraction bulbs contain vesicles, damaged mitochondria, disrupted microtubules, disrupted neurofilaments, and ‘flocculent’ material [S].

lJltrastructura1 evidence from the retracting dorsal column projection provides a more complete picture of the changes associated with swelling in retracting axons [24]. The first alterations in the deprived axons are observed several days after the target lesion. These changes include degenerating mitochondria and increases in the incidence of both multi- vesicular bodies and coated vesicles. By ten days after the lesion, axonal swellings are present. These spherical structures contain numerous organelles, including lysosome-like structures and disorganized microtubules. The ultrastructural changes have been interpreted to mean that target deprivation leads to axon membrane endocytosis and degradation (termed ‘autophagia’ by the authors), which, in turn, causes branch retraction [24]. Concurrently, clear synaptic vesicles become scant at terminal varicosities

while dense core vesicles, which originate in the cell body, increase in number. Synaptophysin staining of target- deprived axons also changed, rather than the normal punctate staining at synaptic terminals it became diffuse, suggesting that the cell body was still supplying the retracting nerve branches with material. Indeed, Marty and Paschanski [24] suggest that the axonal swellings may be the result of an imbalance between supply from the cell body, which remains normal, and demand by the nerve terminals, which is quite low secondary to a reduction in branches and synapses.

Regulation of axon caliber There is an extensive literature on the way axon caliber changes with age (radial axonal growth) and disease, although little of this information is directly related to the changes associated with synapse elimination or target deprivation. Axon caliber is correlated with the number and spacing of neurofilaments in cross section (for a review, see [ZS]). Mutant animals lacking the neurofilament light


Figure 3

Glial and target influences on axon caliber

(a) Glial influences on axon caliber

Neurofilaments

(b) Target influences on axon caliber

Current Opinion ID Neurobiology

Glial and target influences on axon caliber. (a) The caliber of an axon is related to presence of the appropriate class of glia (i.e. oligodendroglia in the CNS and myelinating Schwann cells in the PNS). In situations where the appropriate glial cells are not available because of developmental constraints, disease or experimental manipulation, axon caliber is small. The glial-associated increase in axon caliber results in greater numbers of neurofilaments and their spacing becomes less dense. (b) The caliber of an axon is also related to the number of distal branches. Axons that generate additional branches increase their caliber; conversely, axons that withdraw branches atrophy,

chain [29,30] or lacking the ability to transport neurofila- merits into axons [31] have abnormally small axon calibers. Whereas mutants that overexpress neurofilaments can have larger than normal caliber [32]. These facts suggest that nemofilament number and spacing are being effected by synapse elimination and target deprivation.

The regulation of axon caliber is related in some way to the number of branches the axon supports distally (Figure 3). Motor axons that branch to innervate large numbers of muscle fibers (large motor units) are known to have faster conduction velocity (and hence a larger caliber) than axons that branch to innervate fewer fibers [33]. This correlation has been experimentally tested by forcing sympathetic ganglion cell axons to innervate more targets than normal. Such axons increased their diameter and, unlike normal axons, became myelinated [34].

The role of glia It is likely that glial cells present at the synapse or along the axon also play a role in maintaining the normal caliber of axons (Figure 3). In the postnatal developing optic

nerve, as the retinal ganglion cell axons come in contact with oligodendrocytes, their caliber increases about four- fold. The increase is seen only in the regions of the optic nerve distal to the lamina cribosa, where oligodendrocytes have access to optic axons and the axons become myelinated. This increase is not a consequence of myelin formation; rather, it is attributable to direct contact with glial cells because it also takes place in mutant mice unable to form compacted myelin [35]. The increase in caliber is associated with an increase in the number and spacing of neurofilaments. Other work has shown that regions of sensory axons that are not myelinated (i.e. the nodes of Ranvier and the stem process attaching the myelinated axon to the dorsal root ganglion cell soma) have fewer neurofilaments and closer spacing than else- where [36,37]. In addition, the neurofilaments are more phosphorylated in the myelinated segments than the unmyelinated regions.

The nature of the signal glial cells use to regulate the caliber of axons is not known, although recent work has suggested that myelin-associated glycoprotein (MAG) may be involved [38]. It is not known whether branch retraction may also be triggered by alterations in glial-axonal signaling. It is known that at some sites undergoing competitive synapse elimination, both the axon branch and glial cell are removed, although which is following which is not known [ll]. Experimentally induced Schwann cell sprouting by pharmacological means can cause nerve terminals to vacate synaptic sites, presumably as they grow to follow the glial processes [39*]. This perturbation of axonal branches by glia suggests that glial cells may play a role in branch maintenance and retraction.

The two sets of results described above showing regulation of axon morphology by targets and by glia provide two alternative mechanisms for eliciting axonal changes during development. The many experiments in which target cell death causes axon retraction, however, make it likely that at least changes in postsynaptic cell signaling are involved in developmental axon retraction. A crucial question then is what are the signals that target cells use to verify their existence and health to innervating axons? The ability of protein synthesis blockade in muscle cells to initiate axonal atrophy and retraction suggests that the proximate cause

of axonal changes is the absence of a constitutively active signal. One popular idea is that target-derived neurotrophins or other growth factors might be this signal [40,41]. Target-derived nerve growth factor (NGF) was the first target-derived agent postulated to signal to innervating neurons. Target-derived NGF not only regulates the survival of innervating neurons, but, as its name implies, it also directly effects axons [42]. Of relevance here is that NGF may be able to prevent axon atrophy of the proximal regions of damaged sensory axons ([43,44]; however, see [4.5]), and its absence has been implicated as causally related to the withdrawal of synapses from axotomized sympathetic ganglion cells [46].


Although NGF is certainly not the retrograde signal at the neuromuscular junction, the putative signal has remained elusive. Experimental expression of glial cell line derived neurotrophic factor (GDNF) in muscle fibers has been shown to induce hyper-multiple innervation in development and increased terminal sprouting in reinnervated adult muscles [47’,48]. However, a number of other factors have also been implicated [49], and presently no single growth factor has been shown to be absolutely necessary for axon branch maintenance. An alternative idea is that retrograde signaling is mediated by contact, and, therefore, severance of an adhesive bond between nerve and synaptic site is sufficient to cause nerve retraction and atrophy. Such a contact-mediated mechanism has been suggested for climbing fiber retraction in the cerebellum [18,19], and it is relevant that atrophic branches at developing neuromuscular junctions have often been observed remote from the synaptic site [lo’]. Although the nature of the critical adhesive signal is not known, several studies have implicated a proteolytic cascade in promoting synapse withdrawal [SO-5’21.

Conclusions Because the constellation of changes that axons undergo during naturally occurring retraction are similar to those observed following target deprivation, it is likely that target alterations are the cause of developmental axon retraction. The way in which target cells signal their presence is not known. Evidence suggests alterations in the glial-axon axis and/or alterations in the target-axon axis directly affect axon caliber and branching. Whether target cells signal axons (or glia) by retrograde trophic or contact- mediated signaling remains to be determined. The nearly universal and morphologically equivalent effects of target deprivation on axons throughout the developing and adult mammalian nervous system suggest that the axon retraction reaction is a general property of axons that are deprived of target support.

Acknowledgements The authors acknowledge grants from the National Institutes of Health and the Muscular Dystrophy Association for support of our own research.

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Axonal atrophy: The retraction reaction