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Article ; Online: Chronic muscle recordings reveal recovery of forelimb function in spinal injured female rats after cortical epidural stimulation combined with rehabilitation and chondroitinase ABC.

Sinopoulou, Eleni / Spejo, Aline Barroso / Roopnarine, Naomi / Burnside, Emily R / Bartus, Katalin / De Winter, Fred / McMahon, Stephen B / Bradbury, Elizabeth J

Journal of neuroscience research

2022 Volume 100, Issue 11, Page(s) 2055–2076

Abstract: Cervical level spinal cord injury (SCI) can severely impact upper limb muscle function, which is typically assessed in the clinic using electromyography (EMG). Here, we established novel preclinical methodology for EMG assessments of muscle function ... ...

Abstract	Cervical level spinal cord injury (SCI) can severely impact upper limb muscle function, which is typically assessed in the clinic using electromyography (EMG). Here, we established novel preclinical methodology for EMG assessments of muscle function after SCI in awake freely moving animals. Adult female rats were implanted with EMG recording electrodes in bicep muscles and received bilateral cervical (C7) contusion injuries. Forelimb muscle activity was assessed by recording maximum voluntary contractions during a grip strength task and cortical motor evoked potentials in the biceps. We demonstrate that longitudinal recordings of muscle activity in the same animal are feasible over a chronic post-injury time course and provide a sensitive method for revealing post-injury changes in muscle activity. This methodology was utilized to investigate recovery of muscle function after a novel combination therapy. Cervical contused animals received intraspinal injections of a neuroplasticity-promoting agent (lentiviral-chondroitinase ABC) plus 11 weeks of cortical epidural electrical stimulation (3 h daily, 5 days/week) and behavioral rehabilitation (15 min daily, 5 days/week). Longitudinal monitoring of voluntary and evoked muscle activity revealed significantly increased muscle activity and upper limb dexterity with the combination treatment, compared to a single treatment or no treatment. Retrograde mapping of motor neurons innervating the biceps showed a predominant distribution across spinal segments C5-C8, indicating that treatment effects were likely due to neuroplastic changes in a mixture of intact and injured motor neurons. Thus, longitudinal assessments of muscle function after SCI correlate with skilled reach and grasp performance and reveal functional benefits of a novel combination therapy.
MeSH term(s)	Animals ; Chondroitin ABC Lyase/pharmacology ; Female ; Forelimb/innervation ; Forelimb/physiology ; Muscle, Skeletal ; Rats ; Recovery of Function/physiology ; Spinal Cord Injuries/therapy ; Upper Extremity
Chemical Substances	Chondroitin ABC Lyase (EC 4.2.2.20)
Language	English
Publishing date	2022-08-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	195324-2
ISSN	1097-4547 ; 0360-4012
ISSN (online)	1097-4547
ISSN	0360-4012
DOI	10.1002/jnr.25111
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Zs.A 1232: Show issues

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Article ; Online: Secretion of a mammalian chondroitinase ABC aids glial integration at PNS/CNS boundaries.

Warren, Philippa M / Andrews, Melissa R / Smith, Marc / Bartus, Katalin / Bradbury, Elizabeth J / Verhaagen, Joost / Fawcett, James W / Kwok, Jessica C F

Scientific reports

2020 Volume 10, Issue 1, Page(s) 11262

Abstract: Schwann cell grafts support axonal growth following spinal cord injury, but a boundary forms between the implanted cells and host astrocytes. Axons are reluctant to exit the graft tissue in large part due to the surrounding inhibitory environment ... ...

Abstract	Schwann cell grafts support axonal growth following spinal cord injury, but a boundary forms between the implanted cells and host astrocytes. Axons are reluctant to exit the graft tissue in large part due to the surrounding inhibitory environment containing chondroitin sulphate proteoglycans (CSPGs). We use a lentiviral chondroitinase ABC, capable of being secreted from mammalian cells (mChABC), to examine the repercussions of CSPG digestion upon Schwann cell behaviour in vitro. We show that mChABC transduced Schwann cells robustly secrete substantial quantities of the enzyme causing large-scale CSPG digestion, facilitating the migration and adhesion of Schwann cells on inhibitory aggrecan and astrocytic substrates. Importantly, we show that secretion of the engineered enzyme can aid the intermingling of cells at the Schwann cell-astrocyte boundary, enabling growth of neurites over the putative graft/host interface. These data were echoed in vivo. This study demonstrates the profound effect of the enzyme on cellular motility, growth and migration. This provides a cellular mechanism for mChABC induced functional and behavioural recovery shown in in vivo studies. Importantly, we provide in vitro evidence that mChABC gene therapy is equally or more effective at producing these effects as a one-time application of commercially available ChABC.
MeSH term(s)	Animals ; Astrocytes/metabolism ; Axons/metabolism ; Cell Adhesion ; Cell Movement ; Cells, Cultured ; Central Nervous System/metabolism ; Chondroitin ABC Lyase/metabolism ; Chondroitin Sulfate Proteoglycans/metabolism ; Female ; Genetic Therapy ; Integrins/metabolism ; Lentivirus/enzymology ; Nerve Regeneration/drug effects ; Neurites/metabolism ; Neuroglia/metabolism ; Neurons/metabolism ; Peripheral Nervous System/metabolism ; Rats ; Rats, Sprague-Dawley ; Schwann Cells/metabolism ; Spinal Cord Injuries/physiopathology
Chemical Substances	Chondroitin Sulfate Proteoglycans ; Integrins ; Chondroitin ABC Lyase (EC 4.2.2.20)
Language	English
Publishing date	2020-07-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-67526-0
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Article ; Online: Cellular targets of nitric oxide in the hippocampus.

Bartus, Katalin / Pigott, Beatrice / Garthwaite, John

PloS one

2013 Volume 8, Issue 2, Page(s) e57292

Abstract: In the hippocampus, as in many other CNS areas, nitric oxide (NO) participates in synaptic plasticity, manifested as changes in pre- and/or postsynaptic function. While it is known that these changes are brought about by cGMP following activation of ... ...

Abstract	In the hippocampus, as in many other CNS areas, nitric oxide (NO) participates in synaptic plasticity, manifested as changes in pre- and/or postsynaptic function. While it is known that these changes are brought about by cGMP following activation of guanylyl cyclase-coupled NO receptors attempts to locate cGMP by immunocytochemistry in hippocampal slices in response to NO have failed to detect the cGMP elevation where expected, i.e. in the pyramidal neurones. Instead, astrocytes, unidentified varicose fibres and GABA-ergic nerve terminals are reported to be the prominent NO targets, raising the possibility that NO acts indirectly via other cells. We have re-investigated the distribution of cGMP generated in response to endogenous and exogenous NO in hippocampal slices using immunohistochemistry and new conditions designed to optimise cGMP accumulation and, hence, its detectability. The conditions included use of tissue from the developing rat hippocampus, a potent inhibitor of phosphodiesterase-2, and an allosteric enhancer of the NO-receptive guanylyl cyclase. Under these conditions, cGMP was formed in response to endogenous NO and was found in a population of pyramidal cell somata in area CA3 and subiculum as well as in structures described previously. The additional presence of exogenous NO resulted in hippocampal cGMP reaching the highest level recorded for brain tissue (1700 pmol/mg protein) and in cGMP immunolabelling throughout the pyramidal cell layer. Populations of axons and interneurones were also stained. According with these results, immunohistochemistry for the common NO receptor β1-subunit indicated widespread expression. A similar staining pattern for the α1-subunit with an antibody used previously in the hippocampus and elsewhere, however, proved to be artefactual. The results indicate that the targets of NO in the hippocampus are more varied and extensive than previous evidence had suggested and, in particular, that the pyramidal neurones participating in NO-dependent synaptic plasticity are direct NO targets.
MeSH term(s)	Animals ; Guanylate Cyclase/metabolism ; Hippocampus/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nitric Oxide/metabolism
Chemical Substances	Nitric Oxide (31C4KY9ESH) ; Guanylate Cyclase (EC 4.6.1.2)
Language	English
Publishing date	2013-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0057292
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Article ; Online: ErbB receptor signaling directly controls oligodendrocyte progenitor cell transformation and spontaneous remyelination after spinal cord injury.

Bartus, Katalin / Burnside, Emily R / Galino, Jorge / James, Nicholas D / Bennett, David L H / Bradbury, Elizabeth J

Glia

2019 Volume 67, Issue 6, Page(s) 1036–1046

Abstract: We recently discovered a novel role for neuregulin-1 (Nrg1) signaling in mediating spontaneous regenerative processes and functional repair after spinal cord injury (SCI). We revealed that Nrg1 is the molecular signal responsible for spontaneous ... ...

Abstract	We recently discovered a novel role for neuregulin-1 (Nrg1) signaling in mediating spontaneous regenerative processes and functional repair after spinal cord injury (SCI). We revealed that Nrg1 is the molecular signal responsible for spontaneous functional remyelination of dorsal column axons by peripheral nervous system (PNS)-like Schwann cells after SCI. Here, we investigate whether Nrg1/ErbB signaling controls the unusual transformation of centrally derived progenitor cells into these functional myelinating Schwann cells after SCI using a fate-mapping/lineage tracing approach. Specific ablation of Nrg1-ErbB receptors in central platelet-derived growth factor receptor alpha (PDGFRα)-derived lineage cells (using PDGFRαCreERT2/Tomato-red reporter mice crossed with ErbB3fl/fl/ErbB4fl/fl mice) led to a dramatic reduction in P0-positive remyelination in the dorsal columns following spinal contusion injury. Central myelination, assessed by Olig2 and proteolipid protein expression, was unchanged. Loss of ErbB signaling in PDGFRα lineage cells also significantly impacted the degree of spontaneous locomotor recovery after SCI, particularly in tests dependent on proprioception. These data have important implications, namely (a) cells from the PDGFRα-expressing progenitor lineage (which are presumably oligodendrocyte progenitor cells, OPCs) can differentiate into remyelinating PNS-like Schwann cells after traumatic SCI, (b) this process is controlled by ErbB tyrosine kinase signaling, and (c) this endogenous repair mechanism has significant consequences for functional recovery after SCI. Thus, ErbB tyrosine kinase receptor signaling directly controls the transformation of OPCs from the PDGFRα-expressing lineage into PNS-like functional remyelinating Schwann cells after SCI.
MeSH term(s)	Animals ; ErbB Receptors/deficiency ; ErbB Receptors/genetics ; Mice ; Mice, Transgenic ; Oligodendrocyte Precursor Cells/metabolism ; Recovery of Function/physiology ; Remyelination/physiology ; Schwann Cells/metabolism ; Signal Transduction/physiology ; Spinal Cord Injuries/metabolism ; Spinal Cord Injuries/pathology
Chemical Substances	EGFR protein, mouse (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2019-01-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639414-0
ISSN	1098-1136 ; 0894-1491
ISSN (online)	1098-1136
ISSN	0894-1491
DOI	10.1002/glia.23586
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Zs.A 2345: Show issues

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Article ; Online: Chondroitinase ABC promotes compensatory sprouting of the intact corticospinal tract and recovery of forelimb function following unilateral pyramidotomy in adult mice.

Starkey, Michelle L / Bartus, Katalin / Barritt, Andrew W / Bradbury, Elizabeth J

The European journal of neuroscience

2012 Volume 36, Issue 12, Page(s) 3665–3678

Abstract: Chondroitin sulphate proteoglycans (CSPGs) are extracellular matrix molecules whose inhibitory activity is attenuated by the enzyme chondroitinase ABC (ChABC). Here we assess whether CSPG degradation can promote compensatory sprouting of the intact ... ...

Abstract	Chondroitin sulphate proteoglycans (CSPGs) are extracellular matrix molecules whose inhibitory activity is attenuated by the enzyme chondroitinase ABC (ChABC). Here we assess whether CSPG degradation can promote compensatory sprouting of the intact corticospinal tract (CST) following unilateral injury and restore function to the denervated forelimb. Adult C57BL/6 mice underwent unilateral pyramidotomy and treatment with either ChABC or a vehicle control. Significant impairments in forepaw symmetry were observed following pyramidotomy, with injured mice preferentially using their intact paw during spontaneous vertical exploration of a cylinder. No recovery on this task was observed in vehicle-treated mice. However, ChABC-treated mice showed a marked recovery of function, with forelimb symmetry fully restored by 5 weeks post-injury. Functional recovery was associated with robust sprouting of the uninjured CST, with numerous axons observed crossing the midline in the brainstem and spinal cord and terminating in denervated grey matter. CST fibres in the denervated side of the spinal cord following ChABC treatment were closely associated with the synaptic marker vGlut1. Immunohistochemical assessment of chondroitin-4-sulphate revealed that CSPGs were heavily digested around lamina X, alongside midline crossing axons and in grey matter regions where sprouting axons and reduced peri-neuronal net staining was observed. Thus, we demonstrate that CSPG degradation promotes midline crossing and reinnervation of denervated target regions by intact CST axons and leads to restored function in the denervated forepaw. Enhancing compensatory sprouting using ChABC provides a route to restore function that could be applied to disorders such as spinal cord injury and stroke.
MeSH term(s)	Animals ; Axons/drug effects ; Axons/pathology ; Chondroitin ABC Lyase/metabolism ; Chondroitin ABC Lyase/pharmacology ; Chondroitin ABC Lyase/therapeutic use ; Chondroitin Sulfate Proteoglycans/metabolism ; Chondroitin Sulfates/metabolism ; Denervation ; Forelimb/innervation ; Male ; Mice ; Mice, Inbred C57BL ; Pyramidal Tracts/pathology ; Pyramidal Tracts/physiopathology ; Pyramidal Tracts/surgery ; Spinal Cord Injuries/drug therapy ; Spinal Cord Regeneration/drug effects
Chemical Substances	Chondroitin Sulfate Proteoglycans ; Chondroitin Sulfates (9007-28-7) ; Chondroitin ABC Lyase (EC 4.2.2.20)
Language	English
Publishing date	2012-10-14
Publishing country	France
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	645180-9
ISSN	1460-9568 ; 0953-816X
ISSN (online)	1460-9568
ISSN	0953-816X
DOI	10.1111/ejn.12017
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Zs.A 2548: Show issues

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Article ; Online: Regulation of IL-10 by chondroitinase ABC promotes a distinct immune response following spinal cord injury.

Didangelos, Athanasios / Iberl, Michaela / Vinsland, Elin / Bartus, Katalin / Bradbury, Elizabeth J

The Journal of neuroscience : the official journal of the Society for Neuroscience

2014 Volume 34, Issue 49, Page(s) 16424–16432

Abstract: Chondroitinase ABC (ChABC) has striking effects on promoting neuronal plasticity after spinal cord injury (SCI), but little is known about its involvement in other pathological mechanisms. Recent work showed that ChABC might also modulate the immune ... ...

Abstract	Chondroitinase ABC (ChABC) has striking effects on promoting neuronal plasticity after spinal cord injury (SCI), but little is known about its involvement in other pathological mechanisms. Recent work showed that ChABC might also modulate the immune response by promoting M2 macrophage polarization. Here we investigate in detail the immunoregulatory effects of ChABC after SCI in rats. Initially, we examined the expression profile of 16 M1/M2 macrophage polarization markers at 3 h and 7 d postinjury. ChABC treatment had a clear effect on the immune signature after SCI. More specifically, ChABC increased the expression of the anti-inflammatory cytokine IL-10, accompanied by a reduction in the proinflammatory cytokine IL-12B in injured spinal tissue. These effects were associated with a distinct, IL-10-mediated anti-inflammatory response in ChABC-treated spinal cords. Mechanistically, we show that IL-10 expression is driven by tissue injury and macrophage infiltration, while the p38 MAPK is the central regulator of IL-10 expression in vivo. These findings provide novel insights into the effects of ChABC in the injured spinal cord and explain its immunoregulatory activity.
MeSH term(s)	Animals ; Chondroitin ABC Lyase/administration & dosage ; Chondroitin ABC Lyase/pharmacology ; Chondroitin ABC Lyase/physiology ; Gene Expression Regulation ; Imidazoles/pharmacology ; Immunomodulation/drug effects ; Immunomodulation/physiology ; Inflammation Mediators/metabolism ; Injections, Spinal ; Interleukin-10/biosynthesis ; Interleukin-12/biosynthesis ; Macrophages, Peritoneal/metabolism ; Macrophages, Peritoneal/physiology ; Male ; Proteoglycans/metabolism ; Pyridines/pharmacology ; Rats ; Spinal Cord/drug effects ; Spinal Cord/metabolism ; Spinal Cord Injuries/immunology ; p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors ; p38 Mitogen-Activated Protein Kinases/physiology
Chemical Substances	Imidazoles ; Inflammation Mediators ; Proteoglycans ; Pyridines ; Interleukin-10 (130068-27-8) ; Interleukin-12 (187348-17-0) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Chondroitin ABC Lyase (EC 4.2.2.20) ; SB 203580 (OU13V1EYWQ)
Language	English
Publishing date	2014-12-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.2927-14.2014
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Zs.A 1668: Show issues

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Article ; Online: Cyclin-dependent-like kinase 5 is required for pain signaling in human sensory neurons and mouse models.

Science translational medicine

2020 Volume 12, Issue 551

Abstract: Cyclin-dependent-like kinase 5 ( ...

Abstract	Cyclin-dependent-like kinase 5 (
MeSH term(s)	Animals ; Cyclins ; Disease Models, Animal ; Humans ; Mice ; Pain ; Protein Serine-Threonine Kinases/genetics ; Sensory Receptor Cells ; Signal Transduction
Chemical Substances	Cyclins ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; CDKL5 protein, human (EC 2.7.11.22) ; CDKL5 protein, mouse (EC 2.7.11.22)
Language	English
Publishing date	2020-09-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.aax4846
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Article ; Online: Neuregulin-1 controls an endogenous repair mechanism after spinal cord injury.

Bartus, Katalin / Galino, Jorge / James, Nicholas D / Hernandez-Miranda, Luis R / Dawes, John M / Fricker, Florence R / Garratt, Alistair N / McMahon, Stephen B / Ramer, Matt S / Birchmeier, Carmen / Bennett, David L H / Bradbury, Elizabeth J

Brain : a journal of neurology

2016 Volume 139, Issue Pt 5, Page(s) 1394–1416

Abstract: Following traumatic spinal cord injury, acute demyelination of spinal axons is followed by a period of spontaneous remyelination. However, this endogenous repair response is suboptimal and may account for the persistently compromised function of ... ...

Abstract	Following traumatic spinal cord injury, acute demyelination of spinal axons is followed by a period of spontaneous remyelination. However, this endogenous repair response is suboptimal and may account for the persistently compromised function of surviving axons. Spontaneous remyelination is largely mediated by Schwann cells, where demyelinated central axons, particularly in the dorsal columns, become associated with peripheral myelin. The molecular control, functional role and origin of these central remyelinating Schwann cells is currently unknown. The growth factor neuregulin-1 (Nrg1, encoded by NRG1) is a key signalling factor controlling myelination in the peripheral nervous system, via signalling through ErbB tyrosine kinase receptors. Here we examined whether Nrg1 is required for Schwann cell-mediated remyelination of central dorsal column axons and whether Nrg1 ablation influences the degree of spontaneous remyelination and functional recovery following spinal cord injury. In contused adult mice with conditional ablation of Nrg1, we found an absence of Schwann cells within the spinal cord and profound demyelination of dorsal column axons. There was no compensatory increase in oligodendrocyte remyelination. Removal of peripheral input to the spinal cord and proliferation studies demonstrated that the majority of remyelinating Schwann cells originated within the injured spinal cord. We also examined the role of specific Nrg1 isoforms, using mutant mice in which only the immunoglobulin-containing isoforms of Nrg1 (types I and II) were conditionally ablated, leaving the type III Nrg1 intact. We found that the immunoglobulin Nrg1 isoforms were dispensable for Schwann cell-mediated remyelination of central axons after spinal cord injury. When functional effects were examined, both global Nrg1 and immunoglobulin-specific Nrg1 mutants demonstrated reduced spontaneous locomotor recovery compared to injured controls, although global Nrg1 mutants were more impaired in tests requiring co-ordination, balance and proprioception. Furthermore, electrophysiological assessments revealed severely impaired axonal conduction in the dorsal columns of global Nrg1 mutants (where Schwann cell-mediated remyelination is prevented), but not immunoglobulin-specific mutants (where Schwann cell-mediated remyelination remains intact), providing robust evidence that the profound demyelinating phenotype observed in the dorsal columns of Nrg1 mutant mice is related to conduction failure. Our data provide novel mechanistic insight into endogenous regenerative processes after spinal cord injury, demonstrating that Nrg1 signalling regulates central axon remyelination and functional repair and drives the trans-differentiation of central precursor cells into peripheral nervous system-like Schwann cells that remyelinate spinal axons after injury. Manipulation of the Nrg1 system could therefore be exploited to enhance spontaneous repair after spinal cord injury and other central nervous system disorders with a demyelinating pathology.media-1vid110.1093/brain/aww039_video_abstractaww039_video_abstract.
MeSH term(s)	Animals ; Axons/physiology ; Axons/ultrastructure ; Cell Proliferation ; Demyelinating Diseases/physiopathology ; Female ; Mice ; Mice, Mutant Strains ; Motor Skills/physiology ; Myelin Sheath/physiology ; Myelin Sheath/ultrastructure ; Neural Conduction/physiology ; Neuregulin-1/biosynthesis ; Neuregulin-1/genetics ; Neuregulin-1/physiology ; Protein Isoforms/physiology ; Rats ; Recovery of Function/genetics ; Recovery of Function/physiology ; Schwann Cells/physiology ; Spinal Cord/metabolism ; Spinal Cord/physiopathology ; Spinal Cord/ultrastructure ; Spinal Cord Injuries/genetics ; Spinal Cord Injuries/physiopathology ; Spinal Cord Regeneration/physiology
Chemical Substances	Neuregulin-1 ; Protein Isoforms
Language	English
Publishing date	2016-03-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/aww039
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Article ; Online: Conduction failure following spinal cord injury: functional and anatomical changes from acute to chronic stages.

James, Nicholas D / Bartus, Katalin / Grist, John / Bennett, David L H / McMahon, Stephen B / Bradbury, Elizabeth J

The Journal of neuroscience : the official journal of the Society for Neuroscience

2011 Volume 31, Issue 50, Page(s) 18543–18555

Abstract: In the majority of spinal cord injuries (SCIs), some axonal projections remain intact. We examined the functional status of these surviving axons since they represent a prime therapeutic target. Using a novel electrophysiological preparation, adapted ... ...

Abstract	In the majority of spinal cord injuries (SCIs), some axonal projections remain intact. We examined the functional status of these surviving axons since they represent a prime therapeutic target. Using a novel electrophysiological preparation, adapted from techniques used to study primary demyelination, we quantified conduction failure across a SCI and studied conduction changes over time in adult rats with a moderate severity spinal contusion (150 kdyn; Infinite Horizon impactor). By recording antidromically activated single units from teased dorsal root filaments, we demonstrate complete conduction block in ascending dorsal column axons acutely (1-7 d) after injury, followed by a period of restored conduction over the subacute phase (2-4 weeks), with no further improvements in conduction at chronic stages (3-6 months). By cooling the lesion site, additional conducting fibers could be recruited, thus revealing a population of axons that are viable but unable to conduct under normal physiological conditions. Importantly, this phenomenon is still apparent at the most chronic (6 month) time point. The time course of conduction changes corresponded with changes in behavioral function, and ultrastructural analysis of dorsal column axons revealed extensive demyelination during the period of conduction block, followed by progressive remyelination. A proportion of dorsal column axons remained chronically demyelinated, suggesting that these are the axons recruited with the cooling paradigm. Thus, using a clinically relevant SCI model, we have identified a population of axons present at chronic injury stages that are intact but fail to conduct and are therefore a prime target for therapeutic strategies to restore function.
MeSH term(s)	Action Potentials/physiology ; Animals ; Axons/physiology ; Female ; Neural Conduction/physiology ; Neurons/physiology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/physiopathology ; Spinal Cord Injuries/physiopathology ; Time Factors
Language	English
Publishing date	2011-12-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.4306-11.2011
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Zs.A 1668: Show issues

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Article ; Online: Picomolar nitric oxide signals from central neurons recorded using ultrasensitive detector cells.

Wood, Katherine C / Batchelor, Andrew M / Bartus, Katalin / Harris, Kathryn L / Garthwaite, Giti / Vernon, Jeffrey / Garthwaite, John

The Journal of biological chemistry

2011 Volume 286, Issue 50, Page(s) 43172–43181

Abstract: Nitric oxide (NO) is a widespread signaling molecule with potentially multifarious actions of relevance to health and disease. A fundamental determinant of how it acts is its concentration, but there remains a lack of coherent information on the patterns ...

Abstract	Nitric oxide (NO) is a widespread signaling molecule with potentially multifarious actions of relevance to health and disease. A fundamental determinant of how it acts is its concentration, but there remains a lack of coherent information on the patterns of NO release from its sources, such as neurons or endothelial cells, in either normal or pathological conditions. We have used detector cells having the highest recorded NO sensitivity to monitor NO release from brain tissue quantitatively and in real time. Stimulation of NMDA receptors, which are coupled to activation of neuronal NO synthase, routinely generated NO signals from neurons in cerebellar slices. The average computed peak NO concentrations varied across the anatomical layers of the cerebellum, from 12 to 130 pm. The mean value found in the hippocampus was 200 pm. Much variation in the amplitudes recorded by individual detector cells was observed, this being attributable to their location at variable distances from the NO sources. From fits to the data, the NO concentrations at the source surfaces were 120 pm to 1.4 nm, and the underlying rates of NO generation were 36-350 nm/s, depending on area. Our measurements are 4-5 orders of magnitude lower than reported by some electrode recordings in cerebellum or hippocampus. In return, they establish coherence between the NO concentrations able to elicit physiological responses in target cells through guanylyl cyclase-linked NO receptors, the concentrations that neuronal NO synthase is predicted to generate locally, and the concentrations that neurons actually produce.
MeSH term(s)	Animals ; Cell Line ; Cerebellum/metabolism ; Guanylate Cyclase/metabolism ; Hippocampus/metabolism ; Humans ; Immunohistochemistry ; In Vitro Techniques ; N-Methylaspartate/pharmacology ; Neurons/drug effects ; Neurons/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase/metabolism ; Rats ; Receptors, Glutamate/metabolism ; Signal Transduction/drug effects
Chemical Substances	Receptors, Glutamate ; Nitric Oxide (31C4KY9ESH) ; N-Methylaspartate (6384-92-5) ; Nitric Oxide Synthase (EC 1.14.13.39) ; Guanylate Cyclase (EC 4.6.1.2)
Language	English
Publishing date	2011-10-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M111.289777
Database	MEDical Literature Analysis and Retrieval System OnLINE

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