Download Spontaneous plasticity in the injured spinal cord

Molecular Psychiatry (2002) 7, 9–11
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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-
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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
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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
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Molecular Psychiatry