Site-specific seeding of Lewy pathology induces distinct pre-motor cellular and dendritic vulnerabilities in the cortex
Abstract Circuit-based biomarkers distinguishing the gradual progression of Lewy pathology across synucleinopathies remain unknown. Here, we show that seeding of α-synuclein preformed fibrils in mouse dorsal striatum and motor cortex leads to distinct prodromal-phase cortical dysfunction across mont...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54945-0 |
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| author | Hammad F. Khan Sayan Dutta Alicia N. Scott Shulan Xiao Saumitra Yadav Xiaoling Chen Uma K. Aryal Tamara L. Kinzer-Ursem Jean-Christophe Rochet Krishna Jayant |
| author_facet | Hammad F. Khan Sayan Dutta Alicia N. Scott Shulan Xiao Saumitra Yadav Xiaoling Chen Uma K. Aryal Tamara L. Kinzer-Ursem Jean-Christophe Rochet Krishna Jayant |
| author_sort | Hammad F. Khan |
| collection | DOAJ |
| description | Abstract Circuit-based biomarkers distinguishing the gradual progression of Lewy pathology across synucleinopathies remain unknown. Here, we show that seeding of α-synuclein preformed fibrils in mouse dorsal striatum and motor cortex leads to distinct prodromal-phase cortical dysfunction across months. Our findings reveal that while both seeding sites had increased cortical pathology and hyperexcitability, distinct differences in electrophysiological and cellular ensemble patterns were crucial in distinguishing pathology spread between the two seeding sites. Notably, while beta-band spike-field-coherence reflected a significant increase beginning in Layer-5 and then spreading to Layer-2/3, the rate of entrainment and the propensity of stochastic beta-burst dynamics was markedly seeding location-specific. This beta dysfunction was accompanied by gradual superficial excitatory ensemble instability following cortical, but not striatal, preformed fibrils injection. We reveal a link between Layer-5 dendritic vulnerabilities and translaminar beta event dysfunction, which could be used to differentiate symptomatically similar synucleinopathies. |
| format | Article |
| id | doaj-art-1d4127c6eeb94a9fab1b372c156803bc |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-1d4127c6eeb94a9fab1b372c156803bc2025-01-05T12:36:14ZengNature PortfolioNature Communications2041-17232024-12-0115111910.1038/s41467-024-54945-0Site-specific seeding of Lewy pathology induces distinct pre-motor cellular and dendritic vulnerabilities in the cortexHammad F. Khan0Sayan Dutta1Alicia N. Scott2Shulan Xiao3Saumitra Yadav4Xiaoling Chen5Uma K. Aryal6Tamara L. Kinzer-Ursem7Jean-Christophe Rochet8Krishna Jayant9Weldon School of Biomedical Engineering, West LafayettePurdue Institute for Integrative Neuroscience, Purdue UniversityPurdue Institute for Integrative Neuroscience, Purdue UniversityWeldon School of Biomedical Engineering, West LafayetteWeldon School of Biomedical Engineering, West LafayettePurdue Institute for Integrative Neuroscience, Purdue UniversityDepartment of Comparative Pathobiology, Purdue UniversityWeldon School of Biomedical Engineering, West LafayettePurdue Institute for Integrative Neuroscience, Purdue UniversityWeldon School of Biomedical Engineering, West LafayetteAbstract Circuit-based biomarkers distinguishing the gradual progression of Lewy pathology across synucleinopathies remain unknown. Here, we show that seeding of α-synuclein preformed fibrils in mouse dorsal striatum and motor cortex leads to distinct prodromal-phase cortical dysfunction across months. Our findings reveal that while both seeding sites had increased cortical pathology and hyperexcitability, distinct differences in electrophysiological and cellular ensemble patterns were crucial in distinguishing pathology spread between the two seeding sites. Notably, while beta-band spike-field-coherence reflected a significant increase beginning in Layer-5 and then spreading to Layer-2/3, the rate of entrainment and the propensity of stochastic beta-burst dynamics was markedly seeding location-specific. This beta dysfunction was accompanied by gradual superficial excitatory ensemble instability following cortical, but not striatal, preformed fibrils injection. We reveal a link between Layer-5 dendritic vulnerabilities and translaminar beta event dysfunction, which could be used to differentiate symptomatically similar synucleinopathies.https://doi.org/10.1038/s41467-024-54945-0 |
| spellingShingle | Hammad F. Khan Sayan Dutta Alicia N. Scott Shulan Xiao Saumitra Yadav Xiaoling Chen Uma K. Aryal Tamara L. Kinzer-Ursem Jean-Christophe Rochet Krishna Jayant Site-specific seeding of Lewy pathology induces distinct pre-motor cellular and dendritic vulnerabilities in the cortex Nature Communications |
| title | Site-specific seeding of Lewy pathology induces distinct pre-motor cellular and dendritic vulnerabilities in the cortex |
| title_full | Site-specific seeding of Lewy pathology induces distinct pre-motor cellular and dendritic vulnerabilities in the cortex |
| title_fullStr | Site-specific seeding of Lewy pathology induces distinct pre-motor cellular and dendritic vulnerabilities in the cortex |
| title_full_unstemmed | Site-specific seeding of Lewy pathology induces distinct pre-motor cellular and dendritic vulnerabilities in the cortex |
| title_short | Site-specific seeding of Lewy pathology induces distinct pre-motor cellular and dendritic vulnerabilities in the cortex |
| title_sort | site specific seeding of lewy pathology induces distinct pre motor cellular and dendritic vulnerabilities in the cortex |
| url | https://doi.org/10.1038/s41467-024-54945-0 |
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