1. Neuroscience

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
https://doi.org/10.7554/eLife.95577
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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.

Data availability

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).

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.

Metrics

  • 1,409
    views
  • 235
    downloads
  • 0
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Categories and tags

Research organism

Further reading

    1. Neuroscience

    Post-retrieval noradrenergic activation impairs subsequent memory depending on cortico-hippocampal reactivation

    Hendrik Heinbockel, Gregor Leicht ... Lars Schwabe
    Research Article

    When retrieved, seemingly stable memories can become sensitive to significant events, such as acute stress. The mechanisms underlying these memory dynamics remain poorly understood. Here, we show that noradrenergic stimulation after memory retrieval impairs subsequent remembering, depending on hippocampal and cortical signals emerging during retrieval. In a three-day study, we measured brain activity using fMRI during initial encoding, 24 hr-delayed memory cueing followed by pharmacological elevations of glucocorticoid or noradrenergic activity, and final recall. While post-retrieval glucocorticoids did not affect subsequent memory, the impairing effect of noradrenergic arousal on final recall depended on hippocampal reactivation and category-level reinstatement in the ventral temporal cortex during memory cueing. These effects did not require a reactivation of the original memory trace and did not interact with offline reinstatement during rest. Our findings demonstrate that, depending on the retrieval-related neural reactivation of memories, noradrenergic arousal after retrieval can alter the future accessibility of consolidated memories.

    1. Neuroscience

    Nutritional state-dependent modulation of insulin-producing cells in Drosophila

    Rituja S Bisen, Fathima Mukthar Iqbal ... Jan M Ache
    Research Article

    Insulin plays a key role in metabolic homeostasis. Drosophila insulin-producing cells (IPCs) are functional analogues of mammalian pancreatic beta cells and release insulin directly into circulation. To investigate the in vivo dynamics of IPC activity, we quantified the effects of nutritional and internal state changes on IPCs using electrophysiological recordings. We found that the nutritional state strongly modulates IPC activity. IPC activity decreased with increasing periods of starvation. Refeeding flies with glucose or fructose, two nutritive sugars, significantly increased IPC activity, whereas non-nutritive sugars had no effect. In contrast to feeding, glucose perfusion did not affect IPC activity. This was reminiscent of the mammalian incretin effect, where glucose ingestion drives higher insulin release than intravenous application. Contrary to IPCs, Diuretic hormone 44-expressing neurons in the pars intercerebralis (DH44PINs) responded to glucose perfusion. Functional connectivity experiments demonstrated that these DH44PINs do not affect IPC activity, while other DH44Ns inhibit them. Hence, populations of autonomously and systemically sugar-sensing neurons work in parallel to maintain metabolic homeostasis. Accordingly, activating IPCs had a small, satiety-like effect on food-searching behavior and reduced starvation-induced hyperactivity, whereas activating DH44Ns strongly increased hyperactivity. Taken together, we demonstrate that IPCs and DH44Ns are an integral part of a modulatory network that orchestrates glucose homeostasis and adaptive behavior in response to shifts in the metabolic state.