Ca2+-induced myelin pathology precedes axonal spheroid formation and is mediated in part by store-operated Ca2+ entry after spinal cord injury
[INLINE:1] The formation of axonal spheroid is a common feature following spinal cord injury. To further understand the source of Ca2+ that mediates axonal spheroid formation, we used our previously characterized ex vivo mouse spinal cord model that allows precise perturbation of extracellular Ca2+....
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Medknow Publications
2023-01-01
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| Series: | Neural Regeneration Research |
| Subjects: | |
| Online Access: | http://www.nrronline.org/article.asp?issn=1673-5374;year=2023;volume=18;issue=12;spage=2720;epage=2726;aulast=Ames |
| _version_ | 1797773680660447232 |
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| author | Spencer Ames Kia Adams Mariah E Geisen David P Stirling |
| author_facet | Spencer Ames Kia Adams Mariah E Geisen David P Stirling |
| author_sort | Spencer Ames |
| collection | DOAJ |
| description | [INLINE:1]
The formation of axonal spheroid is a common feature following spinal cord injury. To further understand the source of Ca2+ that mediates axonal spheroid formation, we used our previously characterized ex vivo mouse spinal cord model that allows precise perturbation of extracellular Ca2+. We performed two-photon excitation imaging of spinal cords isolated from Thy1YFP+ transgenic mice and applied the lipophilic dye, Nile red, to record dynamic changes in dorsal column axons and their myelin sheaths respectively. We selectively released Ca2+ from internal stores using the Ca2+ ionophore ionomycin in the presence or absence of external Ca2+. We reported that ionomycin dose-dependently induces pathological changes in myelin and pronounced axonal spheroid formation in the presence of normal 2 mM Ca2+ artificial cerebrospinal fluid. In contrast, removal of external Ca2+ significantly decreased ionomycin-induced myelin and axonal spheroid formation at 2 hours but not at 1 hour after treatment. Using mice that express a neuron-specific Ca2+ indicator in spinal cord axons, we confirmed that ionomycin induced significant increases in intra-axonal Ca2+, but not in the absence of external Ca2+. Periaxonal swelling and the resultant disruption in the axo-myelinic interface often precedes and is negatively correlated with axonal spheroid formation. Pretreatment with YM58483 (500 nM), a well-established blocker of store-operated Ca2+ entry, significantly decreased myelin injury and axonal spheroid formation. Collectively, these data reveal that ionomycin-induced depletion of internal Ca2+ stores and subsequent external Ca2+ entry through store-operated Ca2+ entry contributes to pathological changes in myelin and axonal spheroid formation, providing new targets to protect central myelinated fibers. |
| first_indexed | 2024-03-12T22:09:58Z |
| format | Article |
| id | doaj.art-6a901a257627426db104d581c6c6cb9d |
| institution | Directory Open Access Journal |
| issn | 1673-5374 |
| language | English |
| last_indexed | 2024-03-12T22:09:58Z |
| publishDate | 2023-01-01 |
| publisher | Wolters Kluwer Medknow Publications |
| record_format | Article |
| series | Neural Regeneration Research |
| spelling | doaj.art-6a901a257627426db104d581c6c6cb9d2023-07-23T16:11:37ZengWolters Kluwer Medknow PublicationsNeural Regeneration Research1673-53742023-01-0118122720272610.4103/1673-5374.373656Ca2+-induced myelin pathology precedes axonal spheroid formation and is mediated in part by store-operated Ca2+ entry after spinal cord injurySpencer AmesKia AdamsMariah E GeisenDavid P Stirling[INLINE:1] The formation of axonal spheroid is a common feature following spinal cord injury. To further understand the source of Ca2+ that mediates axonal spheroid formation, we used our previously characterized ex vivo mouse spinal cord model that allows precise perturbation of extracellular Ca2+. We performed two-photon excitation imaging of spinal cords isolated from Thy1YFP+ transgenic mice and applied the lipophilic dye, Nile red, to record dynamic changes in dorsal column axons and their myelin sheaths respectively. We selectively released Ca2+ from internal stores using the Ca2+ ionophore ionomycin in the presence or absence of external Ca2+. We reported that ionomycin dose-dependently induces pathological changes in myelin and pronounced axonal spheroid formation in the presence of normal 2 mM Ca2+ artificial cerebrospinal fluid. In contrast, removal of external Ca2+ significantly decreased ionomycin-induced myelin and axonal spheroid formation at 2 hours but not at 1 hour after treatment. Using mice that express a neuron-specific Ca2+ indicator in spinal cord axons, we confirmed that ionomycin induced significant increases in intra-axonal Ca2+, but not in the absence of external Ca2+. Periaxonal swelling and the resultant disruption in the axo-myelinic interface often precedes and is negatively correlated with axonal spheroid formation. Pretreatment with YM58483 (500 nM), a well-established blocker of store-operated Ca2+ entry, significantly decreased myelin injury and axonal spheroid formation. Collectively, these data reveal that ionomycin-induced depletion of internal Ca2+ stores and subsequent external Ca2+ entry through store-operated Ca2+ entry contributes to pathological changes in myelin and axonal spheroid formation, providing new targets to protect central myelinated fibers.http://www.nrronline.org/article.asp?issn=1673-5374;year=2023;volume=18;issue=12;spage=2720;epage=2726;aulast=Amesaxonal degeneration; axonal spheroid formation; ionomycin; store-operated calcium entry; myelin; nile red; peri-axonal swelling |
| spellingShingle | Spencer Ames Kia Adams Mariah E Geisen David P Stirling Ca2+-induced myelin pathology precedes axonal spheroid formation and is mediated in part by store-operated Ca2+ entry after spinal cord injury Neural Regeneration Research axonal degeneration; axonal spheroid formation; ionomycin; store-operated calcium entry; myelin; nile red; peri-axonal swelling |
| title | Ca2+-induced myelin pathology precedes axonal spheroid formation and is mediated in part by store-operated Ca2+ entry after spinal cord injury |
| title_full | Ca2+-induced myelin pathology precedes axonal spheroid formation and is mediated in part by store-operated Ca2+ entry after spinal cord injury |
| title_fullStr | Ca2+-induced myelin pathology precedes axonal spheroid formation and is mediated in part by store-operated Ca2+ entry after spinal cord injury |
| title_full_unstemmed | Ca2+-induced myelin pathology precedes axonal spheroid formation and is mediated in part by store-operated Ca2+ entry after spinal cord injury |
| title_short | Ca2+-induced myelin pathology precedes axonal spheroid formation and is mediated in part by store-operated Ca2+ entry after spinal cord injury |
| title_sort | ca2 induced myelin pathology precedes axonal spheroid formation and is mediated in part by store operated ca2 entry after spinal cord injury |
| topic | axonal degeneration; axonal spheroid formation; ionomycin; store-operated calcium entry; myelin; nile red; peri-axonal swelling |
| url | http://www.nrronline.org/article.asp?issn=1673-5374;year=2023;volume=18;issue=12;spage=2720;epage=2726;aulast=Ames |
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