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.

Reviewing Editor

  1. Sacha B Nelson, Brandeis University, United States

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).

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.

Metrics

  • 847
    views
  • 177
    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

    Experience transforms crossmodal object representations in the anterior temporal lobes

    Aedan Yue Li, Natalia Ladyka-Wojcik ... Morgan D Barense
    Research Article Updated

    Combining information from multiple senses is essential to object recognition, core to the ability to learn concepts, make new inferences, and generalize across distinct entities. Yet how the mind combines sensory input into coherent crossmodal representations – the crossmodal binding problem – remains poorly understood. Here, we applied multi-echo fMRI across a 4-day paradigm, in which participants learned three-dimensional crossmodal representations created from well-characterized unimodal visual shape and sound features. Our novel paradigm decoupled the learned crossmodal object representations from their baseline unimodal shapes and sounds, thus allowing us to track the emergence of crossmodal object representations as they were learned by healthy adults. Critically, we found that two anterior temporal lobe structures – temporal pole and perirhinal cortex – differentiated learned from non-learned crossmodal objects, even when controlling for the unimodal features that composed those objects. These results provide evidence for integrated crossmodal object representations in the anterior temporal lobes that were different from the representations for the unimodal features. Furthermore, we found that perirhinal cortex representations were by default biased toward visual shape, but this initial visual bias was attenuated by crossmodal learning. Thus, crossmodal learning transformed perirhinal representations such that they were no longer predominantly grounded in the visual modality, which may be a mechanism by which object concepts gain their abstraction.

    1. Neuroscience
    2. Stem Cells and Regenerative Medicine

    SAFB regulates hippocampal stem cell fate by targeting Drosha to destabilize Nfib mRNA

    Pascal Forcella, Niklas Ifflander ... Verdon Taylor
    Research Article

    Neural stem cells (NSCs) are multipotent and correct fate determination is crucial to guarantee brain formation and homeostasis. How NSCs are instructed to generate neuronal or glial progeny is not well understood. Here we addressed how murine adult hippocampal NSC fate is regulated and describe how Scaffold Attachment Factor B (SAFB) blocks oligodendrocyte production to enable neuron generation. We found that SAFB prevents NSC expression of the transcription factor Nuclear Factor I/B (NFIB) by binding to sequences in the Nfib mRNA and enhancing Drosha-dependent cleavage of the transcripts. We show that increasing SAFB expression prevents oligodendrocyte production by multipotent adult NSCs, and conditional deletion of Safb increases NFIB expression and oligodendrocyte formation in the adult hippocampus. Our results provide novel insights into a mechanism that controls Drosha functions for selective regulation of NSC fate by modulating the post-transcriptional destabilization of Nfib mRNA in a lineage-specific manner.

    1. Neuroscience

    Action sequence learning, habits, and automaticity in obsessive-compulsive disorder

    Paula Banca, Maria Herrojo Ruiz ... Trevor W Robbins
    Research Article

    This study investigates the goal/habit imbalance theory of compulsion in obsessive-compulsive disorder (OCD), which postulates enhanced habit formation, increased automaticity, and impaired goal/habit arbitration. It directly tests these hypotheses using newly developed behavioral tasks. First, OCD patients and healthy participants were trained daily for a month using a smartphone app to perform chunked action sequences. Despite similar procedural learning and attainment of habitual performance (measured by an objective automaticity criterion) by both groups, OCD patients self-reported higher subjective habitual tendencies via a recently developed questionnaire. Subsequently, in a re-evaluation task assessing choices between established automatic and novel goal-directed actions, both groups were sensitive to re-evaluation based on monetary feedback. However, OCD patients, especially those with higher compulsive symptoms and habitual tendencies, showed a clear preference for trained/habitual sequences when choices were based on physical effort, possibly due to their higher attributed intrinsic value. These patients also used the habit-training app more extensively and reported symptom relief post-study. The tendency to attribute higher intrinsic value to familiar actions may be a potential mechanism leading to compulsions and an important addition to the goal/habit imbalance hypothesis in OCD. We also highlight the potential of smartphone app training as a habit reversal therapeutic tool.