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Hyperactive somatostatin interneurons contribute to excitotoxicity in neurodegenerative disorders

Nature Neuroscience volume 19, pages 557559 (2016) | Download Citation

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative disorders whose pathogenesis remains largely unknown. Using TDP-43A315T mice, an ALS and FTD model with marked cortical pathology, we found that hyperactive somatostatin interneurons disinhibited layer 5 pyramidal neurons (L5-PNs) and contributed to their excitotoxicity. Focal ablation of somatostatin interneurons efficiently restored normal excitability of L5-PNs and alleviated neurodegeneration, suggesting a new therapeutic target for ALS and FTD.

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Acknowledgements

This research was supported by Jackson Lab Startup Funds (D.-T.L.), 1R21 NS075382-01A1 (Y.L. and G.A.C.), and the Intramural Research Program of the National Institute on Drug Abuse (D.-T.L.).

Author information

Author notes

    • Wen Zhang
    •  & Lifeng Zhang

    These authors contributed equally to this work.

Affiliations

  1. Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA.

    • Wen Zhang
    • , Lifeng Zhang
    • , Bo Liang
    • , Yun Li
    •  & Da-Ting Lin
  2. The Jackson Laboratory, Bar Harbor, Maine, USA.

    • David Schroeder
    • , Zhong-wei Zhang
    • , Gregory A Cox
    •  & Da-Ting Lin

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Contributions

Y.L., D.-T.L., W.Z. and L.Z. designed the study and wrote the manuscript. W.Z. and L.Z. performed all of the experiments and analysis. B.L. helped with data analysis. D.S. maintained some mouse colonies. G.A.C. and Z.Z. advised on experiments and manuscript preparation.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Yun Li or Da-Ting Lin.

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DOI

https://doi.org/10.1038/nn.4257

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