SRF-deficient astrocytes provide neuroprotection in mouse models of excitotoxicity and neurodegeneration

  1. Surya Chandra Rao Thumu
  2. Monika Jain
  3. Sumitha Soman
  4. Soumen Das
  5. Vijaya Verma
  6. Arnab Nandi
  7. David H Gutmann
  8. Balaji Jayaprakash
  9. Deepak Nair
  10. James P Clement
  11. Swananda Marathe
  12. Narendrakumar Ramanan  Is a corresponding author
  1. Indian Institute of Science Bangalore, India
  2. Jawaharlal Nehru Centre for Advanced Scientific Research, India
  3. Washington University in St. Louis, United States
  4. University of Exeter, United Kingdom
  5. Indian Institute of Technology Dharwad, India

Abstract

Reactive astrogliosis is a common pathological hallmark of central nervous system (CNS) injury, infection, and neurodegeneration, where reactive astrocytes can be protective or detrimental to normal brain functions. Currently, the mechanisms regulating neuroprotective astrocytes and the extent of neuroprotection are poorly understood. Here, we report that conditional deletion of serum response factor (SRF) in adult astrocytes causes reactive-like hypertrophic astrocytes throughout the mouse brain. These SrfGFAP-ERCKO astrocytes do not affect neuron survival, synapse numbers, synaptic plasticity or learning and memory. However, the brains of Srf knockout mice exhibited neuroprotection against kainic-acid induced excitotoxic cell death. Relevant to human neurodegenerative diseases, SrfGFAP-ERCKO astrocytes abrogate nigral dopaminergic neuron death and reduce b-amyloid plaques in mouse models of Parkinson's and Alzheimer's disease, respectively. Taken together, these findings establish SRF as a key molecular switch for the generation of reactive astrocytes with neuroprotective functions that attenuate neuronal injury in the setting of neurodegenerative diseases.

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All data generated or analysed during this study are included in the manuscript and supporting file

Article and author information

Author details

  1. Surya Chandra Rao Thumu

    Centre for Neuroscience, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  2. Monika Jain

    Centre for Neuroscience, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  3. Sumitha Soman

    Centre for Neuroscience, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  4. Soumen Das

    Centre for Neuroscience, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6422-0238
  5. Vijaya Verma

    Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  6. Arnab Nandi

    Centre for Neuroscience, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  7. David H Gutmann

    Department of Neurology, Washington University in St. Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3127-5045
  8. Balaji Jayaprakash

    Centre for Neuroscience, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4442-6981
  9. Deepak Nair

    Centre for Neuroscience, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  10. James P Clement

    University of Exeter, Exeter, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Swananda Marathe

    Department of Biosciences and Bioengineering, Indian Institute of Technology Dharwad, Karnataka, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2539-366X
  12. Narendrakumar Ramanan

    Centre for Neuroscience, Indian Institute of Science Bangalore, Bangalore, India
    For correspondence
    naren@iisc.ac.in
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6088-9599

Funding

Department of Science and Technology, Ministry of Science and Technology, India (DST/SJF/LSA-01/2012-2013)

  • Narendrakumar Ramanan

Science and Engineering Research Board (CRG/2019/006899)

  • Narendrakumar Ramanan

Department of Biotechnology, Ministry of Science and Technology, India (BT/PR27952/INF/22/212/2018)

  • Deepak Nair

Science and Engineering Research Board (EMR/2015/001946)

  • James P Clement

Department of Science and Technology, Ministry of Science and Technology, India (DST/INSPIRE/04-I/2016-000002)

  • Swananda Marathe

Science and Engineering Research Board (PDF/2017/001385)

  • Surya Chandra Rao Thumu

University Grants Commission

  • Monika Jain

University Grants Commission

  • Soumen Das

Council for Scientific and Industrial Research , India

  • Arnab Nandi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All the procedures in this study were performed according to the rules and guidelines of the Committee for the Purpose of Control and Supervision of Experimental Animals (CPCSEA), India. The research protocol was approved by the Institutional Animal Ethics Committee (IAEC) of the Indian Institute of Science (Protocol numbers: CAF/Ethics/596/2018 and CAF/Ethics/731/2020).

Reviewing Editor

  1. Sacha B Nelson, Brandeis University, United States

Version history

  1. Preprint posted: May 17, 2023 (view preprint)
  2. Received: December 27, 2023
  3. Accepted: January 15, 2024
  4. Accepted Manuscript published: January 30, 2024 (version 1)
  5. Version of Record published: February 9, 2024 (version 2)

Copyright

© 2024, Thumu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Surya Chandra Rao Thumu
  2. Monika Jain
  3. Sumitha Soman
  4. Soumen Das
  5. Vijaya Verma
  6. Arnab Nandi
  7. David H Gutmann
  8. Balaji Jayaprakash
  9. Deepak Nair
  10. James P Clement
  11. Swananda Marathe
  12. Narendrakumar Ramanan
(2024)
SRF-deficient astrocytes provide neuroprotection in mouse models of excitotoxicity and neurodegeneration
eLife 13:e95577.
https://doi.org/10.7554/eLife.95577

Share this article

https://doi.org/10.7554/eLife.95577

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