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Molecular Psychiatry (2002) 7, 9–11 2002 Nature Publishing Group All rights reserved 1359-4184/02 $15.00 www.nature.com/mp NEWS & COMMENTARY Spontaneous plasticity in the injured spinal cord— implications for repair strategies Following spinal cord injury (SCI), the disruption of descending and ascending axonal pathways causes loss of motor, sensory and autonomic function. The ultimate goal of neural repair strategies after SCI is to reestablish a critical number of re-connections between supraspinal and spinal neurons to promote recovery of neurological function. Recovery of function after SCI has traditionally been thought to require long-distance axonal regeneration from the brain to the distal, isolated segment of the spinal cord, and vice versa (Figure 1). In this scenario, neurons first need to survive the injury, then their cut axons must overcome an inhospitable milieu and extend through or around the CNS lesion site, reenter Figure 1 Regeneration following complete spinal cord injury. Illustrated is the descending corticospinal system which controls voluntary fine motor movements. (a) Neurons of the CST originate in the primary motor cortex and project caudally through the brainstem, where the majority of projections cross to the contralateral side. Axon collaterals form synapses at segmental spinal level directly with motoneurons or indirectly through interneurons. Following a complete SCI (illustrated in red), axon fragments caudal to the lesion undergo Wallerian degeneration; synapses below the injury level disappear. (b) To reestablish synaptic connections with target neurons below the injury level, severed axons need to pass the lesion site, reenter the caudal spinal cord and find appropriate target neurons at segmental level with which to form new synapses. Correspondence: MH Tuszynski, MD, PhD, Department of Neurosciences-0626, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. E-mail: mtuszyns얀ucsd.edu the caudal spinal cord, choose a correct target among literally millions of potentially incorrect targets, and form functional synapses. Some experimental strategies have resulted in reports of long-distance axonal regeneration and functional improvement to some degree,1 although the underlying neuroanatomical basis for the functional improvement in these studies remains to be fully understood. But is long-distance axonal regeneration the only mechanism likely to bring about functional recovery, even after such severe events as spinal cord injury? Not necessarily. Several types of so-called ‘injury-induced plasticity’, or rearrangements of the nervous system in response to injury, have been known for decades to generate functional recovery. Among these mechanisms are ‘unmasking’ of synapses or pathways that may ordinarily be inactive; ‘denervation hypersensitivity’, in which the target of a partially lesioned projection produces a greater number of receptors to bind a reduced number of available neurotransmitter molecules; and ‘compensatory collateral sprouting’, wherein the injured distal components of axons that are spared by a lesion sprout to occupy adjacent synapses vacated by a lesioned neighboring axon. The unmasking form of plasticity can occur very rapidly—within minutes of an injury—and has been documented on the electrophysiological level to occur in primate sensory cortex following digit amputation.2 Both denervation hypersensitivity and compensatory collateral sprouting take more time to develop, in some cases evolving over weeks, months or even years. In Parkinson’s disease, for example, dopamine receptors increase in number in the striatum as a function of chronic reductions in nigral inputs.3 In Alzheimer’s disease, chronic degeneration of entorhinal cortical inputs to the hippocampus results in compensatory sprouting of cholinergic and kainate inputs.4 The denervation hypersensitivity in Parkinson’s disease is likely to be functionally beneficial, forestalling clinical signs of Parkinson’s disease for a period that could last up to several years. On the other hand, compensatory collateral sprouting in the hippocampus in Alzheimer’s disease may in fact not be functionally beneficial, and could even be deleterious. Thus, injury-induced plasticity can be beneficial, neutral, or deleterious. In the case of spinal cord injury, up to 51% of clinical injuries may be functionally incomplete (National Spinal Cord Injury Statistical Center), raising the possibility that compensatory responses from spared systems may represent a mechanism for generating return of function over time. Indeed, even the majority of clinically complete spinal cord injury patients (ie, hav- News & Commentary 10 ing an absence of sensory and motor function below the level of injury) exhibit spared rims of white matter extending in continuity across the spinal cord lesion site.5 Further, it is notable that many patients with spinal cord injuries exhibit some recovery of function over weeks and months after injury.6 The degree of recovery is typically modest, but can occasionally be extensive. This parallels in time course the often striking degree of functional recovery that can be observed in humans after head trauma and stroke. What is the mechanism of this recovery? Previous studies in rodents demonstrated that lesions of inputs to the hippocampus, sensory cortex, motor cortex, and red nucleus can be followed by compensatory collateral sprouting.7 Recently we investigated whether intrinsic circuitry of the spinal cord, like that of the cortex and brainstem (see Figure 2), could also undergo compensatory sprouting after injury, and whether such sprouting, if present, resulted in functional recovery.8 Adult rodents were subjected to lesions of more than 95% of the corticospinal projection by removing the dorsal corticospinal tract in the cervical spinal cord. This resulted in an acute reduction in the rats’ ability to reach in a highly coordinated manner for a food pellet reward. Within 4 weeks, however, the rats’ ability to retrieve food pellets improved significantly, showing no statistical difference from the function of unlesioned rodents. Analysis of the spinal cord revealed that the small remaining ventral component of the corticospinal tract that was present in the cervical spinal cord of lesioned rats exhibited a 330% increase in numbers of putative synaptic contacts with motor neurons in the spinal cord ventral gray matter. We interpreted this spontaneous but short-distance axonal response to represent compensatory collateral sprouting. Notably, if the dorsal corticospinal tract was lesioned and animals were allowed to recover over 4 weeks, and then the ventral corticospinal tract was subsequently lesioned, functional recovery was abolished. Functional recovery also failed to occur if both the dorsal and ventral corticospinal tracts were lesioned simultaneously, or if the entire corticospinal tract was lesioned in the medulla. Thus, following lesions of greater than 95% of axons of the corticospinal tract in the cervical spinal cord, spontaneous structural rearrangements occur that correlate with functional recovery. Such sprouting, which occurs over relatively short distances rather than the long distances that are targeted in regeneration studies, may be a mechanism accounting for the delayed improvement in function that occurs in many people with spinal cord injuries, stroke or head trauma. That short distance growth and plasticity might generate functional recovery may not be entirely surprising. Species known to regenerate their spinal cords, such as the lamprey and the lizard, appear to re-extend axons across spinal cord transection sites, but rather than regenerating axons for long distances beyond the transection site, they form polysynaptic relays that Molecular Psychiatry Figure 2 Regeneration following incomplete spinal cord injury. (a) Analysis of injured human spinal cords revealed that in the majority of cases some white matter continuity across the lesion site can be found. These spared long-distance projecting axons represent the prerequisite for structural reorganization. (b) Corticospinal neurons, which are disrupted by the SCI, reorient axon collaterals horizontally to form new intracortical synapses. (c) At brainstem level, severed corticospinal neurons form new synapses with motor nuclei (red nucleus, pontine nuclei) mediating similar motor function, whose descending projections are spared by the spinal cord lesion. (d) Caudal to the lesion site, spared axons of descending motor pathways send out axon collaterals to form new synapses with motoneurons at segmental level. conduct electrophysiological impulses to distal locomotor pattern generators in the spinal cord. The existence of spontaneous structural and functional plasticity in the spinal cord raises the possibility that this mechanism could be a target for experimental enhancement as a means of further enhancing axonal growth and, potentially, functional recovery, after SCI. Plasticity is known to occur rostral to sites of spinal cord injury in the brainstem and brain;9 the enhancement of plasticity below the injury site might prove beneficial, particularly if combined with other approaches for enhancing axonal growth after SCI. Neurotrophic factors are proteins that regulate neuronal survival, axonal growth and synaptic plasticity. Neurotrophic factors have been widely used to promote axonal regeneration in the injured CNS. Several News & Commentary studies reported structural regeneration associated with partial functional recovery after the administration of the neurotrophic factors brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3).10 The exact structural correlates for the observed functional recovery remain to be elucidated. Evidence from studies with neurotrophin knockout mice or specific neutralization of neurotrophins suggests that neurotrophic factors promote collateral sprouting and terminal field innervation rather than long-distance axonal regeneration per se.11 Thus, enhanced collateral sprouting with synaptic rearrangements of spared axonal projections may have accounted for the functional recovery observed after neurotrophic factor application to the injured spinal cord. Future studies may logically target enhancement of collateral sprouting and synaptic rearrangement as a mechanism to generate morphological and functional recovery. Growth-associated proteins have been identified in the injured peripheral nervous system (PNS) and appear to be required for successful axonal regeneration. Expression of these growth-associated proteins, in particular GAP-43, is minimal in the injured CNS. Overexpression of GAP-43 in axotomized cerebellar Purkinje-cells induces axonal sprouting in vitro. Coexpression of GAP-43 and another growth-associated protein, CAP-43, promoted regeneration of dorsal root ganglion neurons in the injured adult mouse spinal The continuous intracerebroventricular cord.12 infusion of the purine nucleoside inosine induced the upregulation of GAP-43 after incomplete spinal cord injury, which was paralleled by significant sprouting of uninjured corticospinal axons into the hemisected CST.13 Studies in lower vertebrates suggest that inosine promotes axonal regeneration through a common purine-sensitive pathway. Collectively these data indicate that expression of growth-associated proteins enhances sprouting of injured CNS axons. It remains to be determined whether the observed sprouting is linked with appropriate synaptic rearrangements at spinal segmental level and with functional recovery. The myelin-associated molecules NI-35/-25014 and myelin-associated glycoprotein (MAG)15 have been identified as inhibitors of axonal regrowth in the adult mammalian CNS that limit spontaneous plasticity in the injured adult CNS. Application of neutralizing antibodies directed against NI-250 reportedly directly promoted axonal regeneration in the injured CNS, although more recently the neutralization of myelinassociated inhibitors has also been reported to enhance sprouting of corticospinal axons.16 Not all neuronal populations in a CNS environment respond equally to neutralization of myelin-based inhibitory molecules. The neutralization of myelin-associated inhibitory molecules is not sufficient to promote regeneration of injured sensory axons in the adult rat spinal cord,17 raising the possibility that myelin-associated growth inhibitors may not affect all CNS axons equally. Nevertheless, neutralization of myelin-associated inhibitory molecules likely represents what will eventually be an important component of a multi-targeted approach to promote structural reorganization in the injured spinal cord. Structural correlates for spontaneous recovery have been identified in the CNS, together with molecules determining the basis of structural reorganization. The goal is now to apply these molecules in a spatially and temporally appropriate fashion, and as combined therapies, to promote more substantial structural and functional regeneration after SCI. 11 Acknowledgements This work was supported by the NIH, Veterans Affairs, Canadian Spinal Research Organization, the Swiss Institut International de Recherche en Paraplégie Geneva, and the Hollfelder Foundation. N Weidner1,2 and MH Tuszynski1,3 Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; 2 Department of Neurology, University of Regensburg, 93053, Germany; 3 Veterans Affairs Medical Center, San Diego, CA 92161, USA 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Horner PJ, Gage FH. Nature 2000; 407: 963–970. Merzenich MM et al. J Comp Neurol 1984; 224: 591–605. Rinne UK et al. Mov Disord 1990; 5: 55–59. Geddes JW et al. Science 1985; 230: 1179–1181. Kakulas BA. J Spinal Cord Med 1999; 22: 119–124. Frankel HK. In: Swash M (ed). 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