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Site-specific seeding of Lewy pathology induces distinct pre-motor cellular and dendritic vulnerabilities in the cortex

Author

Listed:
  • Hammad F. Khan

    (West Lafayette
    Purdue University)

  • Sayan Dutta

    (Purdue University
    Purdue University)

  • Alicia N. Scott

    (Purdue University
    Purdue University)

  • Shulan Xiao

    (West Lafayette
    Purdue University)

  • Saumitra Yadav

    (West Lafayette
    Purdue University)

  • Xiaoling Chen

    (Purdue University
    Purdue University)

  • Uma K. Aryal

    (Purdue University
    Purdue University)

  • Tamara L. Kinzer-Ursem

    (West Lafayette
    Purdue University)

  • Jean-Christophe Rochet

    (Purdue University
    Purdue University)

  • Krishna Jayant

    (West Lafayette
    Purdue University)

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.

Suggested Citation

  • 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, 2024. "Site-specific seeding of Lewy pathology induces distinct pre-motor cellular and dendritic vulnerabilities in the cortex," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54945-0
    DOI: 10.1038/s41467-024-54945-0
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    References listed on IDEAS

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