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0000-0002-8683-2937
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Central Nervous System | Neurocognitive Patterns and Neural Networks | Cell Neurochemistry | Neurosciences
Publisher: Mary Ann Liebert Inc
Date: 15-11-2013
Abstract: Neurofilaments (NFs) have been proposed to have a significant role in attempted axonal regeneration following a variety of forms of injury. The NF triplet proteins of the central nervous system are comprised of light (NF-L), medium (NF-M) and heavy (NF-H) chains and are part of the type IV intermediate filament family. We sought to define the role of NF-L in the neuronal response to trauma and regeneration by examining the effect of total absence of the NF-L protein on neuronal maturation and response to axotomy. This study utilized an in vitro model comprising relatively mature cortical murine neurons derived from either wild-type embryonic (E15) mice or mice with a genetic knockout of NF-L (NF-L KO). Whilst NF-L KO neurons developed to relative maturity at a comparable rate to wild-type control neurons, NF-L KO neurons demonstrated relatively increased expression of α-internexin and decreased expression of NF-M. Further, we demonstrate that α-internexin co-immunoprecipitates with the NF binding protein NDel1 in NFL-KO cortical neurons in vitro. Following localized axotomy, NF-L KO neurons demonstrated reduced amyloid precursor protein accumulation in damaged neurites as well as a significant reduction in the number of axons regenerating (4.79+/-0.58 sprouts) in comparison to control preparations (10.47+/-1.11 sprouts) (p<0.05). These studies indicate that NFs comprising NF-L have a dynamic role in the reactive and regenerative changes in axons following injury.
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.MCN.2015.02.006
Abstract: Neuronal cytoskeletal alterations, in particular the loss and misalignment of microtubules, are considered a hallmark feature of the degeneration that occurs after traumatic brain injury (TBI). Therefore, microtubule-stabilizing drugs are attractive potential therapeutics for use following TBI. The best-known drug in this category is Paclitaxel, a widely used anti-cancer drug that has produced promising outcomes when employed in the treatment of various animal models of nervous system trauma. However, Paclitaxel is not ideal for the treatment of patients with TBI due to its limited blood-brain barrier (BBB) permeability. Herein we have characterized the effect of the brain penetrant microtubule-stabilizing agent Epothilone D (Epo D) on post-injury axonal sprouting in an in vitro model of CNS trauma. Epo D was found to modulate axonal sprout number in a dose dependent manner, increasing the number of axonal sprouts generated post-injury. Elevated sprouting was observed when analyzing the total population of injured neurons, as well as in selective analysis of Thy1-YFP-labeled excitatory neurons. However, we found no effect of Epo D on axonal sprout length or outgrowth speed. These findings indicate that Epo D specifically affects injury-induced axonal sprout generation, but not net growth. Our investigation demonstrates that primary cultures of cortical neurons are tolerant of Epo D exposure, and that Epo D significantly increases their regenerative response following structural injury. Therefore Epo D may be a potent therapeutic for enhancing regeneration following CNS injury. This article is part of a Special Issue entitled 'Traumatic Brain Injury'.
Publisher: Springer Science and Business Media LLC
Date: 15-03-2017
DOI: 10.1038/SREP44461
Abstract: Increasing evidence indicates an excitatory/inhibitory imbalance may have a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Impaired inhibitory circuitry is consistently reported in the motor cortex of both familial and sporadic patients, closely associated with cortical hyperexcitability and ALS onset. Inhibitory network dysfunction is presumably mediated by intra-cortical inhibitory interneurons, however, the exact cell types responsible are yet to be identified. In this study we demonstrate dynamic changes in the number of calretinin- (CR) and neuropeptide Y-expressing (NPY) interneurons in the motor cortex of the familial hSOD1 G93A ALS mouse model, suggesting their potential involvement in motor neuron circuitry defects. We show that the density of NPY-populations is significantly decreased by ~17% at symptom onset (8 weeks), and by end-stage disease (20 weeks) is significantly increased by ~30%. Conversely, the density of CR-populations is progressively reduced during later symptomatic stages (~31%) to end-stage (~36%), while CR-expressing interneurons also show alteration of neurite branching patterns at symptom onset. We conclude that a differential capacity for interneurons exists in the ALS motor cortex, which may not be a static phenomenon, but involves early dynamic changes throughout disease, implicating specific inhibitory circuitry.
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.BRAINRES.2009.08.059
Abstract: While functional recovery after injury is limited, it has become evident that the mature central nervous system does retain some ability to regenerate. This study investigated the intrinsic capacity of relatively mature cortical neurons (21 days in vitro) to respond to axonal loss. Neurons, growing as clusters on poly-L-lysine, were completely sheared of axons through chemical and mechanical disruption and transferred to either an intact astrocyte monolayer or a substrate of poly-L-lysine. Injured neurons exhibited a regenerative sprouting response that was independent of neuronal cell ision or neural progenitors, as demonstrated by negative bromodeoxyuridine (BrdU) and the neuronal precursor intermediate filament nestin, labeling. At 24 h after injury, neurons had extended appropriately polarized neurites, demonstrated by compartmentalized microtubule-associated proteins MAP2 and tau immunolabeling. Newly sprouting axons were tipped by growth cones however, growth cones on the tips of sprouting axons (mean area, 26.32 +/- 2.20 microm) were significantly (p<0.05) smaller than their developmental counterparts (mean area, 48.64 +/- 5.9 microm), independent of substrate. Furthermore, live imaging indicated that regenerating neurons exhibited distinct axonal dynamics, with a significant (p<0.05) reduction (70%) in pausing, considered vital for interstitial branching and pathfinding, relative to developmental growth cones. This study indicates that mature cultured cortical pyramidal and interneurons have the intrinsic potential to survive, extend processes, and reestablish neurite polarity following significant physical damage. These results may aid in defining the cellular basis of neuronal structural plasticity and defining the role of astrocyte reactivity in the response to trauma.
Publisher: SAGE Publications
Date: 2012
DOI: 10.1042/AN20110031
Abstract: Glutamate excitotoxicity is a major pathogenic process implicated in many neurodegenerative conditions, including AD (Alzheimer's disease) and following traumatic brain injury. Occurring predominantly from over-stimulation of ionotropic glutamate receptors located along dendrites, excitotoxic axonal degeneration may also occur in white matter tracts. Recent identification of axonal glutamate receptor subunits within axonal nanocomplexes raises the possibility of direct excitotoxic effects on axons. In idual neuronal responses to excitotoxicity are highly dependent on the complement of glutamate receptors expressed by the cell, and the localization of the functional receptors. To enable isolation of distal axons and targeted excitotoxicity, murine cortical neuron cultures were prepared in compartmented microfluidic devices, such that distal axons were isolated from neuronal cell bodies. Within the compartmented culture system, cortical neurons developed to relative maturity at 11 DIV (days in vitro) as demonstrated by the formation of dendritic spines and clustering of the presynaptic protein synaptophysin. The isolated distal axons retained growth cone structures in the absence of synaptic targets, and expressed glutamate receptor subunits. Glutamate treatment (100 μM) to the cell body chamber resulted in widespread degeneration within this chamber and degeneration of distal axons in the other chamber. Glutamate application to the distal axon chamber triggered a lesser degree of axonal degeneration without degenerative changes in the untreated somal chamber. These data indicate that in addition to current mechanisms of indirect axonal excitotoxicity, the distal axon may be a primary target for excitotoxicity in neurodegenerative conditions.
Publisher: Wiley
Date: 10-2007
DOI: 10.1111/J.1460-9568.2007.05845.X
Abstract: Excitotoxicity has been implicated as a potential cause of neuronal degeneration in amyotrophic lateral sclerosis (ALS). It has not been clear how excitotoxic injury leads to the hallmark pathological changes of ALS, such as the abnormal accumulation of filamentous proteins in axons. We have investigated the effects of overactivation of excitatory receptors in rodent neurons maintained in long-term culture. Excitotoxicity, mediated principally via non-N-methyl-D-aspartate (NMDA) receptors, caused axonal swelling and accumulation of cytoskeletal proteins in the distal segments of the axons of cultured spinal, but not cortical, neurons. Axonopathy only occurred in spinal neurons maintained for 3 weeks in vitro, indicating that susceptibility to axonal pathology may be related to relative maturity of the neuron. Excitotoxic axonopathy was associated with the aberrant colocalization of phosphorylated and dephosphorylated neurofilament proteins, indicating that disruption to the regulation of phosphorylation of neurofilaments may lead to their abnormal accumulation. These data provide a strong link between excitotoxicity and the selective pattern of axonopathy of lower motor neurons that underlies neuronal dysfunction in ALS.
Publisher: Wiley
Date: 09-11-2020
DOI: 10.1111/JNC.15214
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.BRAINRESBULL.2009.08.004
Abstract: There has been growing interest in the axon as the initial focus of pathological change in a number of neurodegenerative diseases of the central nervous system. This review concentrates on three major neurodegenerative conditions--amyotrophic lateral sclerosis, multiple sclerosis and Alzheimer's disease--with emphasis on key cellular changes that may underlie early axonal dysfunction and pathology and, potentially, the degeneration of neurons. In particular, this review will address recent data that indicate that the main pathological stimuli for these conditions, though often not definitively determined, result in an initial perturbation of the axon and its cytoskeleton, which then results in slow neuronal degeneration and loss of connectivity. The identification of a degenerative process initiated in the axon may provide new therapeutic targets for early intervention to inhibit the grim outcomes related to the progression of these diseases.
Publisher: Wiley
Date: 26-08-2021
DOI: 10.1111/EJN.15422
Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease commonly treated with riluzole, a small molecule that may act via modulation of glutamatergic neurotransmission. However, riluzole only modestly extends lifespan for people living with ALS, and its precise mechanisms of action remain unclear. Most ALS cases are characterised by accumulation of cytoplasmic TAR DNA binding protein of 43 kDa (TDP‐43), and understanding the effects of riluzole in models that closely recapitulate TDP‐43 pathology may provide insights for development of improved therapeutics. We therefore investigated the effects of riluzole in female transgenic mice that inducibly express nuclear localisation sequence (NLS)‐deficient human TDP‐43 in neurons ( NEFH ‐tTA/ tetO ‐hTDP‐43ΔNLS, ‘rNLS8’, mice). Riluzole treatment from the first day of hTDP‐43ΔNLS expression did not alter disease onset, weight loss or performance on multiple motor behavioural tasks. Riluzole treatment also did not alter TDP‐43 protein levels, solubility or phosphorylation. Although we identified a significant decrease in GluA2 and GluA3 proteins in the cortex of rNLS8 mice, riluzole did not ameliorate this disease‐associated molecular phenotype. Likewise, riluzole did not alter the disease‐associated atrophy of hindlimb muscle in rNLS8 mice. Finally, riluzole treatment beginning after disease onset in rNLS8 mice similarly had no effect on progression of late‐stage disease or animal survival. Together, we demonstrate specific glutamatergic receptor alterations and muscle fibre‐type changes reminiscent of ALS in female rNLS8 mice, but riluzole had no effect on these or any other disease phenotypes. Future targeting of pathways related to accumulation of TDP‐43 pathology may be needed to develop better treatments for ALS.
Publisher: Future Medicine Ltd
Date: 12-2015
DOI: 10.2217/NMT.15.49
Abstract: In amyotrophic lateral sclerosis, motor neuron hyperexcitability and inhibitory dysfunction is emerging as a potential causative link in the dysfunction and degeneration of the motoneuronal circuitry that characterizes the disease. Interneurons, as key regulators of excitability, may mediate much of this imbalance, yet we know little about the way in which inhibitory deficits perturb excitability. In this review, we explore inhibitory control of excitability and the potential contribution of altered inhibition to amyotrophic lateral sclerosis disease processes and vulnerabilities, identifying important windows of therapeutic opportunity and potential interventions, specifically targeting inhibitory control at key disease stages.
Publisher: Springer New York
Date: 2015
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.JNEUMETH.2013.06.002
Abstract: Modelling the complex process of neuromuscular signalling is key to understanding not only normal circuit function but also importantly the mechanisms underpinning a range of degenerative diseases. We describe a novel in vitro model of the lower motor neuron-neuromuscular junction circuit, incorporating primary spinal motor neurons, supporting glia and skeletal muscle. This culture model is designed to spatially mimic the unique anatomical and cellular interactions of this circuit in compartmented microfluidic devices, such that the glial cells are located with motor neuron cell bodies in the cell body chamber and motor neuron axons extend to a distal chamber containing skeletal muscle cells whilst simultaneously allowing targeted intervention. This model is suitable for use in conjunction with a range of downstream experimental approaches and could also be modified to utilise other cellular sources including appropriate immortal cell lines, cells derived from transgenic models of disease and also patient derived stem cells.
Publisher: The Company of Biologists
Date: 2019
DOI: 10.1242/DMM.038109
Abstract: Altered cortical excitability and synapse dysfunction are early pathogenic events in amyotrophic lateral sclerosis (ALS) patients and animal models. Recent studies propose an important role for TAR DNA binding protein 43 (TDP-43), a protein whose mislocalization and aggregation are key pathological features of ALS, at the neuronal synapse. However, the relationship between ALS-linked TDP-43 mutations, excitability, and synaptic function is not fully understood. Here, we investigate the role of ALS-linked mutant TDP-43 in synapse formation by examining the morphological, immunocytochemical and excitability profile of transgenic mouse primary cortical pyramidal neurons over-expressing human TDP-43A315T. In TDP-43A315T cortical neurons, dendritic spine density was significantly reduced compared to wild type (WT) controls. TDP-43A315T over-expression increased the total amount of the AMPA glutamate receptor subunit GluR1, yet the localization of GluR1 to the dendritic spine was reduced. These post-synaptic changes were coupled with a decrease in the amount of the pre-synaptic marker synaptophysin colocalized with dendritic spines. Interestingly, action potential generation was reduced in TDP-43A315T pyramidal neurons. This work reveals a crucial effect of the over-expression mutation TDP-43A315T on the formation of synaptic structures and the recruitment of GluR1 to the synaptic membrane. This pathogenic effect may be mediated by cytoplasmic mislocalization of TDP-43A315T. Loss of synaptic GluR1, and reduced excitability within pyramidal neurons, implicates hypoexcitability and attenuated synaptic function in the pathogenic decline of neuronal function in TDP-43-associated ALS. Further studies into the mechanisms underlying AMPA receptor-mediated excitability changes within the ALS cortical circuitry may yield novel therapeutic targets for treatment of this devastating disease.
Publisher: Wiley
Date: 29-08-2023
DOI: 10.1002/ACN3.51885
Abstract: Neuropeptide Y (NPY) is a 36 amino acid peptide widely considered to provide neuroprotection in a range of neurodegenerative diseases. In the fatal motor neuron disease amyotrophic lateral sclerosis (ALS), recent evidence supports a link between NPY and ALS disease processes. The goal of this study was to determine the therapeutic potential and role of NPY in ALS, harnessing the brain‐targeted intranasal delivery of the peptide, previously utilised to correct motor and cognitive phenotypes in other neurological conditions. To confirm the association with clinical disease characteristics, NPY expression was quantified in post‐mortem motor cortex tissue of ALS patients and age‐matched controls. The effect of NPY on ALS cortical pathophysiology was investigated using slice electrophysiology and multi‐electrode array recordings of SOD1 G93A cortical cultures in vitro. The impact of NPY on ALS disease trajectory was investigated by treating SOD1 G93A mice intranasally with NPY and selective NPY receptor agonists and antagonists from pre‐symptomatic and symptomatic phases of disease. In the human post‐mortem ALS motor cortex, we observe a significant increase in NPY expression, which is not present in the somatosensory cortex. In vitro, we demonstrate that NPY can ameliorate ALS hyperexcitability, while brain‐targeted nasal delivery of NPY and a selective NPY Y1 receptor antagonist modified survival and motor deficits specifically within the symptomatic phase of the disease in the ALS SOD1 G93A mouse. Taken together, these findings highlight the capacity for non‐invasive brain‐targeted interventions in ALS and support antagonism of NPY Y1Rs as a novel strategy to improve ALS motor function.
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.NEUROBIOLAGING.2009.04.004
Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating disorder involving loss of movement due to degeneration of motor neurons. Studies suggest that in ALS axonal dysfunction precedes the death of motor neurons. Pathologically, ALS is characterized by neurofilamentous swellings (spheroids) within the axons of motor neurons. However, the causes of this axonopathy and possible resulting axonal dysfunction are not known. Using a novel model of cultured mouse motor neurons, we have determined that these neurons are susceptible to proximal axonopathy, which is related to the glial environment. This axonopathy showed remarkable similarity, both morphologically and neurochemically, to spheroids that develop over months in SOD1(G93A) transgenic mice. Focal ubiquitination, as well as perturbations of neurofilaments and microtubules, occurred in the axonal spheroid-like swellings in vitro, and visualization of mitochondrial dynamics demonstrated that axonopathy resulted in impaired axonal transport. These data provide strong evidence for the involvement of non-neuronal cells in axonal dysfunction in ALS. This cell culture model may be of benefit for the development of therapeutic interventions directed at axonal preservation.
Publisher: The Company of Biologists
Date: 03-2015
DOI: 10.1242/DMM.018606
Abstract: There is a desperate need for targeted therapeutic interventions that slow the progression of amyotrophic lateral sclerosis (ALS). ALS is a disorder with heterogeneous onset, which then leads to common final pathways involving multiple neuronal compartments that span both the central and peripheral nervous system. It is believed that excitotoxic mechanisms might play an important role in motor neuron death in ALS. However, little is known about the mechanisms by which excitotoxicity might lead to the neuromuscular junction degeneration that characterizes ALS, or about the site at which this excitotoxic cascade is initiated. Using a novel compartmentalised model of site-specific excitotoxin exposure in lower motor neurons in vitro, we found that spinal motor neurons are vulnerable to somatodendritic, but not axonal, excitotoxin exposure. Thus, we developed a model of somatodendritic excitotoxicity in vivo using osmotic mini pumps in Thy-1-YFP mice. We demonstrated that in vivo cell body excitotoxin exposure leads to significant motor neuron death and neuromuscular junction (NMJ) retraction. Using confocal real-time live imaging of the gastrocnemius muscle, we found that NMJ remodelling preceded excitotoxin-induced NMJ degeneration. These findings suggest that excitotoxicity in the spinal cord of in iduals with ALS might result in a die-forward mechanism of motor neuron death from the cell body outward, leading to initial distal plasticity, followed by subsequent pathology and degeneration.
Publisher: Mary Ann Liebert Inc
Date: 09-2017
Abstract: It is clear that even mild forms of traumatic brain injury (TBI) can have lasting cognitive effects however, the specific cellular changes responsible for the functional deficits remain poorly understood. Previous studies suggest that not all neurons respond in the same way and that changes to neuronal architecture may be subtype specific. The current study aimed to characterize the response of interneurons to TBI. To model TBI in vitro, the neurites of primary cortical neurons were transected at 15 days in vitro. In response, calretinin
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.JCHEMNEU.2016.03.003
Abstract: Degeneration of the distal axon and neuromuscular junction (NMJ) is considered a key and early feature of the pathology that accompanies motor neuron loss in people with amyotrophic lateral sclerosis (ALS). The mutant SOD1(G93A) mouse replicates many features of the disease, however the sequence of events resulting in degeneration of the neuromuscular circuitry remains unknown. Furthermore, despite widespread degenerative neuronal pathology throughout the spinal cord in this model, hindlimb motor function is lost before forelimb function. We investigated axons and NMJs in the hindlimb (gastrocnemius) and forelimb (extensor) muscles in the high copy number mutant SOD1(G93A)xYFP (yellow fluorescent protein) mouse. We found that distal axonal and NMJ alterations were present prior to previously reported functional symptom onset in this strain. Indeed, increased branch complexity as well as colocalisation between pre- and post-synaptic markers indicated widespread early axonal and NMJ alterations in the hindlimb. Immunohistochemical analysis demonstrated that the colocalisation of the scaffolding proteins nestin, LRP-4, dystrophin and rapsyn were diminished before post-synaptic receptors in the gastrocnemius, and the degree of loss differed between proteins. Analysis of the forelimb muscle revealed axonal and NMJ degeneration at a late, post symptomatic stage, as well as novel differences in NMJ morphology, with reduced complexity. Furthermore, post-synaptic scaffolding proteins were preserved in the forelimb compared with the hindlimb. Analysis of protein levels indicated an increase in LRP-4, dystrophin and rapsyn in post symptomatic skeletal muscle that may suggest ongoing attempts at repair. This study indicates that axonal and NMJ degeneration in the SOD1 model of ALS is a complex and evolving sequence of events. We provide evidence that YFP can detect morphological and plastic alterations in the SOD1(G93A) mouse, and that the pre- and post-synaptic integrity of the NMJ plays an important role in the pathogenic mechanisms of ALS.
Publisher: Public Library of Science (PLoS)
Date: 04-05-2017
Publisher: Frontiers Media SA
Date: 02-03-2016
Publisher: Oxford University Press (OUP)
Date: 05-08-2016
Abstract: TDP-43 is a major protein component of pathological neuronal inclusions that are present in frontotemporal dementia and amyotrophic lateral sclerosis. We report that TDP-43 plays an important role in dendritic spine formation in the cortex. The density of spines on YFP+ pyramidal neurons in both the motor and somatosensory cortex of Thy1-YFP mice, increased significantly from postnatal day 30 (P30), to peak at P60, before being pruned by P90. By comparison, dendritic spine density was significantly reduced in the motor cortex of Thy1-YFP::TDP-43A315T transgenic mice prior to symptom onset (P60), and in the motor and somatosensory cortex at symptom onset (P90). Morphological spine-type analysis revealed that there was a significant impairment in the development of basal mushroom spines in the motor cortex of Thy1-YFP::TDP-43A315T mice compared to Thy1-YFP control. Furthermore, reductions in spine density corresponded to mislocalisation of TDP-43 immunoreactivity and lowered efficacy of synaptic transmission as determined by electrophysiology at P60. We conclude that mutated TDP-43 has a significant pathological effect at the dendritic spine that is associated with attenuated neural transmission.
Publisher: Wiley
Date: 29-08-2007
DOI: 10.1111/J.1460-9568.2007.05750.X
Abstract: While long-distance regeneration may be limited in mammalian species, it is becoming apparent that damaged mature neurons retain some capacity for attempted regeneration and that the adult CNS is not entirely inhibitory to axon growth. Our investigations show that there are critical intrinsic features of postinjury axonal regeneration that differ from initial axon development, and that these distinct differences may account for the limited and inappropriate regenerative response that currently characterizes the mature CNS. We compared the neurochemical and dynamic characteristics of developing axons to relatively mature regenerating axons, utilizing an in vitro model of axonal transection to long-term cultured rat cortical neurons. Immunolabelling studies revealed that regenerating and developing axons have a similar localization of cytoskeletal proteins, but the tips of regenerating axons, although morphologically similar, were smaller with reduced fillopodial extension, relative to developmental growth cones. Live imaging demonstrated that regenerating axons exhibited significantly less outgrowth than developmental neurites. Furthermore, growth cones of regenerating axons had a significant reduction in pausing, considered vital for interstitial branching and pathfinding, than did developmental growth cones. In addition, unlike developing axons, the regenerating axons were unresponsive to the growth factors BDNF and GDNF. Thus, although similar in their cytoskeletal composition, the growth cones of regenerative sprouts differed from their developmental counterparts in their size, their dynamic behaviour and their ability to respond to critical growth factors. These intrinsic differences may account for the inability of post-traumatic locally sprouting axons to make accurate pathway decisions and successfully respond to trauma.
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.BRAINRES.2012.05.018
Abstract: Axonal degeneration is a prominent feature of amyotrophic lateral sclerosis (ALS) both in lower motor nerves as well as descending white matter axons in the spinal cord of human patients. Although the pathology of lower motor axonal degeneration has been described in both human ALS and related transgenic animal models, few studies have examined the pathological features of descending axon degeneration, particularly in mouse models of ALS. We have examined the degeneration of white matter tracts in the G93A mutant superoxide dismutase-1 (mSOD1+) mouse spinal cord white matter from 12 weeks of age to end-stage disease. In a G93A mSOD1 mouse model where green fluorescent protein was expressed in neurons (mSOD1+/GFP+), degeneration of white matter tracts was present from the ventral to dorsolateral funiculi. This pattern of axonal pathology occurred from 16 weeks of age. However, the dorsal funiculus, the site of the major corticospinal tract in mice, showed relatively less degeneration. Immunohistochemical analysis demonstrated that the neurofilament light chain (NFL) and neuronal intermediate filament protein alpha-internexin accumulated in axon swellings in the spinal white matter. Increased levels of alpha-internexin protein, in mSOD1+ mouse spinal cord tissue, were demonstrated by Western blotting. In contrast, degenerating axons did not show obvious accumulations of neurofilament medium and heavy chain proteins (NFM and NFH). These data suggest that white matter degeneration in this mouse model of ALS is widespread and involves a specific molecular signature, particularly the accumulation of NFL and alpha-internexin proteins.
Publisher: Oxford University Press (OUP)
Date: 28-05-2010
Abstract: Accumulating evidence indicates that damage to the adult mammalian brain evokes an array of adaptive cellular responses and may retain a capacity for structural plasticity. We have investigated the cellular and architectural alterations following focal experimental brain injury, as well as the specific capacity for structural remodeling of neuronal processes in a subset of cortical interneurons. Focal acute injury was induced by transient insertion of a needle into the neocortex of anesthetized adult male Hooded-Wistar rats and thy1 green fluorescent protein (GFP) mice. Immunohistochemical, electron microscopy, and bromodeoxyuridine cell proliferation studies demonstrated an active and evolving response of the brain to injury, indicating astrocytic but not neuronal proliferation. Immunolabeling for the neuron-specific markers phosphorylated neurofilaments, α-internexin and calretinin at 7 days post injury (DPI) indicated phosphorylated neurofilaments and α-internexin but not calretinin immunopositive axonal sprouts within the injury site. However, quantitative studies indicated a significant realignment of horizontally projecting dendrites of calretinin-labeled interneurons at 14 DPI. This remodeling was specific to calretinin immunopositive interneurons and did not occur in a subpopulation of pyramidal neurons expressing GFP in the injured mouse cortex. These data show that subclasses of cortical interneurons are capable of adaptive structural remodeling.
No related organisations have been discovered for Catherine Blizzard.
Start Date: 2012
End Date: 2012
Funder: Royal Hobart Hospital Research Foundation
View Funded ActivityStart Date: 2013
End Date: 2013
Funder: Motor Neurone Disease Research Institute of Australia Inc
View Funded ActivityStart Date: 2014
End Date: 2014
Funder: Motor Neurone Disease Research Institute of Australia Inc
View Funded ActivityStart Date: 2014
End Date: 2014
Funder: Brain Foundation
View Funded ActivityStart Date: 2015
End Date: 2015
Funder: Motor Neurone Disease Research Institute of Australia Inc
View Funded ActivityStart Date: 2016
End Date: 2016
Funder: Motor Neurone Disease Research Institute of Australia Inc
View Funded ActivityStart Date: 2017
End Date: 02-2021
Amount: $372,000.00
Funder: Australian Research Council
View Funded Activity