Remodeling of synaptic structures in the motor cortex following spinal cord injury
Introduction
Spinal cord injury (SCI) removes supraspinal input to the spinal motor networks and thus results in a severe and permanent loss of motor function below the injury site. Some degree of functional recovery, however, can be observed without intervention (Bregman and Goldberger, 1983, Burns et al., 1997). Since regeneration of injured axons is extremely limited in mature CNS, spontaneous recovery in motor function appears to be mediated by structural reorganization of spared motor system. This compensatory remodeling occurs at multiple levels of the neuraxis including spinal motor centers, descending supraspinal motor tracts, brainstem, and the motor cortex (Raineteau and Schwab, 2001).
The sensorimotor cortex in adults retains the capability to reorganize in response to alteration in peripheral sensory input or behavioral manipulation (Clark et al., 1988, Nudo et al., 1996). A much greater extent of structural and functional plasticity can be observed after large-scale injuries such as limb amputation or SCI (Jain et al., 1997, Pons et al., 1991). Several lines of evidence suggest that synaptic connectivity in the sensorimotor cortex can be modified after SCI. Spinal lesions in cats and primates reshape the sensory representational map in the cortex (Jain et al., 1997, McKinley et al., 1987). Functional imaging (Bruehlmeier et al., 1998) and transcranial magnetic stimulation (Topka et al., 1991) demonstrated significant alterations in connectivity between the motor cortex and spinal cord in human SCI as well.
The cellular and/or anatomical substrates subserving injury-induced cortical plasticity are not fully understood. Unmasking or potentiation of existing connections may contribute to the plasticity within a short time scale (Hess and Donoghue, 1994, Jacobs and Donoghue, 1991), whereas alteration in cortical connectivity over months to years may involve new growth of axonal and dendritic processes (Darian-Smith and Gilbert, 1994, Florence et al., 1998, Volkmar and Greenough, 1972). Structural remodeling at the level of individual synapses may be another mechanism (Stepanyants et al., 2002). The density of dendritic spines, postsynaptic specializations at the excitatory synapses, is sensitive to a variety of experience or environmental stimuli (Globus et al., 1973, Gould et al., 1990, Moser et al., 1994). Recent in vivo imaging studies have suggested that the appearance and disappearance of spines underlie experience-dependent plasticity during development as well as in adults (Lendvai et al., 2000, Trachtenberg et al., 2002). Not only spine density but also morphology of spine structures is sensitive to various stimuli that are associated with synaptic plasticity (Hayashi and Majewska, 2005, Yuste and Bonhoeffer, 2001). For example, changes in spine neck length were observed after social stimulation or electrical stimulation to evoke long-term potentiation (Coss and Globus, 1978, Fifkova and Anderson, 1981), and changes in morphology or size of spine head were also associated with synaptic plasticity (Desmond and Levy, 1983, Desmond and Levy, 1986, Matsuzaki et al., 2004). It is not known, however, whether remodeling of dendritic spines, particularly spine morphology, is involved in the injury-induced cortical reorganization, and if so, with what time scale this remodeling proceeds after injury.
In this study, we sought to determine whether SCI leads to remodeling of synaptic structures in the motor cortex. For this end, we visualized dendritic spines in the motor cortex using confocal microscopy in fixed slice preparations and examined the spine density and morphology in detail. Since spine morphology such as spine length and head diameter is closely related to functional characteristics of an individual synapse (Kasai et al., 2003, Yuste et al., 2000), the analysis of spine morphology from a large population of dendritic spines also allowed us to infer the potential changes in overall functional properties in the motor cortical network following SCI. Furthermore, we examined correlative changes in expression of various synapse-associated proteins in the motor cortex after SCI, attempting to define a temporal profile of the remodeling process.
Section snippets
Animals and spinal lesion
Adult female Sprague–Dawley rats (200–250 gm; Zivic Inc., Zelienople, PA) were used in this study. They were housed in the Georgetown University Division of Comparative Medicine Facility and all protocols were approved by the Georgetown University Animal Care and Use Committee. Animals received a right cervical overhemisection injury at the C4 level using a procedure modified from that described previously (Bregman et al., 1997). This injury removes the right hemicord plus the left dorsal
Remodeling of dendritic spines in the motor cortex following SCI
To determine whether axotomy at the spinal level alters synaptic structures in the motor cortex, we focused on postsynaptic spine structures and measured density (number per unit length), head diameter, and length of dendritic spines. To more accurately quantify those variables from a large number of spines, we opted to use confocal microscopic imaging on fluorescently labeled neuronal processes, instead of using traditional Golgi staining or electronmicroscopy (EM) analysis. Golgi staining
Discussion
We made several observations that collectively provide evidence that dynamic remodeling of synaptic structures occurs in the motor cortex following SCI. First, the density of postsynaptic spines decreases in the motor cortex at 7 days after SCI followed by a partial recovery by 28 days. Second, spine head diameter increases after SCI with a different time course depending on the layer. Third, SCI leads to a higher proportion of longer spines especially at 28 days, resulting in a roughly 10%
Acknowledgments
We thank Dr. Bogdan Stoica for technical advice for confocal microscopy, Dr. Zhanyan Fu for assistance in DiI labeling, and Dr. Barry Wolfe and Dr. Robert Yasuda for generous supply of NMDA receptor subunit antibodies and technical comments on the immunoblot experiment. We also thank Dr. Thomas Finn and Dr. Daniel Pak for helpful comments on the manuscript, and Dr. Shibao Feng for statistical consultation. This study was supported by NIH grant NS27054.
References (82)
- et al.
Laminar-dependent dendritic spine alterations in the motor cortex of adult rats following callosal transection and forced forelimb use
Neurobiol. Learn. Mem.
(2002) - et al.
Making memories stick: cell-adhesion molecules in synaptic plasticity
Trends Cell Biol.
(2000) - et al.
Infant lesion effect: II. Sparing and recovery of function after spinal cord damage in newborn and adult cats
Brain Res.
(1983) - et al.
Neurotrophic factors increase axonal growth after spinal cord injury and transplantation in the adult rat
Exp. Neurol.
(1997) - et al.
Transplants and neurotrophic factors increase regeneration and recovery of function after spinal cord injury
Prog. Brain Res.
(2002) - et al.
Recovery of ambulation in motor-incomplete tetraplegia
Arch. Phys. Med. Rehabil.
(1997) - et al.
Differential spine loss and regrowth of striatal neurons following multiple forms of deafferentation: a Golgi study
Exp. Neurol.
(1997) - et al.
Synaptic correlates of associative potentiation/depression: an ultrastructural study in the hippocampus
Brain Res.
(1983) - et al.
Stimulation-induced changes in dimensions of stalks of dendritic spines in the dentate molecular layer
Exp. Neurol.
(1981) - et al.
Cervical sprouting of corticospinal fibers after thoracic spinal cord injury accompanies shifts in evoked motor responses
Curr. Biol.
(2001)
Assembly of new individual excitatory synapses: time course and temporal order of synaptic molecule recruitment
Neuron
Regulation of cell adhesion by polysialic acid. Effects on cadherin, immunoglobulin cell adhesion molecule, and integrin function and independence from neural cell adhesion molecule binding or signaling activity
J. Biol. Chem.
Multicolor “DiOlistic” labeling of the nervous system using lipophilic dye combinations
Neuron
Dendritic spine geometry: functional implication and regulation
Neuron
Overgrowth and pruning of dendrites in adult rats recovering from neocortical damage
Brain Res.
Synaptogenesis and dendritic growth in the cortex opposite unilateral sensorimotor cortex damage in adult rats: a quantitative electron microscopic examination
Brain Res.
Structure–stability–function relationships of dendritic spines
Trends Neurosci.
Incomplete spinal cord injury: neuronal mechanisms of motor recovery and hyperreflexia
Arch. Phys. Med. Rehabil.
Reactive synaptogenesis assessed by synaptophysin immunoreactivity is associated with GAP-43 in the dentate gyrus of the adult rat
Exp. Neurol.
Age-dependent capacity for somatosensory cortex reorganization in chronic spinal cats
Brain Res.
PSA-NCAM is required for activity-induced synaptic plasticity
Neuron
Inactivity produces increases in neurotransmitter release and synapse size
Neuron
Spine-neck geometry determines NMDA receptor-dependent Ca2+ signaling in dendrites
Neuron
Polysialic acid in the vertebrate nervous system: a promoter of plasticity in cell–cell interactions
Trends Neurosci.
Dendritic remodeling of dentate granule cells following a combined entorhinal cortex/fimbria fornix lesion
Exp. Neurol.
Geometry and structural plasticity of synaptic connectivity
Neuron
Evidence for a role of dendritic filopodia in synaptogenesis and spine formation
Neuron
Activity-dependent regulation of dendritic spine density on cortical pyramidal neurons in organotypic slice cultures
J. Neurobiol.
The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats
Nat. Neurosci.
Efficacy of rehabilitative experience declines with time after focal ischemic brain injury
J. Neurosci.
How does the human brain deal with a spinal cord injury?
Eur. J. Neurosci.
Receptive fields in the body-surface map in adult cortex defined by temporally correlated inputs
Nature
Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits
Proc. Natl. Acad. Sci. U. S. A.
Spine stems on tectal interneurons in jewel fish are shortened by social stimulation
Science
The dynamics of dendritic structure in developing hippocampal slices
J. Neurosci.
Axonal sprouting accompanies functional reorganization in adult cat striate cortex
Nature
Changes in the postsynaptic density with long-term potentiation in the dentate gyrus
J. Comp. Neurol.
Polysialylated neural cell adhesion molecule promotes remodeling and formation of hippocampal synapses
J. Neurosci.
The motor cortex of the rat: cytoarchitecture and microstimulation mapping
J. Comp. Neurol.
A technique for estimating total spine numbers on Golgi-impregnated dendrites
J. Comp. Neurol.
Synaptogenesis via dendritic filopodia in developing hippocampal area CA1
J. Neurosci.
Cited by (135)
Cortical volume reductions as a sign of secondary cerebral and cerebellar impairment in patients with degenerative cervical myelopathy
2021, NeuroImage: ClinicalCitation Excerpt :For example, a retrograde neuronal degeneration from the location of spinal cord injury has been presumed to cause cortical GM loss (Beaud et al., 2008; Hains et al., 2003). In addition, investigating decreased cortical connectivity and reduced angiogenetic activity may help to explain these secondary impairments in the brain (Kim et al., 2006; Fields, 2008). Other research suggested that reduced activity in neural cells, particular in the somatosensory cortex and due to decreased signal transmission, may lead to atrophy in these areas (Jones, 2000).
Animal Models of Cerebral Changes Secondary to Spinal Cord Injury
2021, World NeurosurgeryThe neuroplasticity marker PSA-NCAM: Insights into new therapeutic avenues for promoting neuroregeneration
2020, Pharmacological ResearchBrain Plasticity in Patients with Spinal Cord Injuries: A Systematic Review
2024, International Journal of Molecular Sciences
- 1
Current address: Brain Disease Research Center, Ajou University School of Medicine, Suwon 443-721, Republic of Korea.