SRF-deficient astrocytes provide neuroprotection in mouse models of excitotoxicity and neurodegeneration
- Indian Institute of Science Bangalore, India
- Jawaharlal Nehru Centre for Advanced Scientific Research, India
- Washington University in St. Louis, United States
- University of Exeter, United Kingdom
- 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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file
Article and author information
Author details
Balaji Jayaprakash
Narendrakumar Ramanan
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.
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SRF-deficient astrocytes provide neuroprotection in mouse models of excitotoxicity and neurodegeneration
eLife 13:e95577.
https://doi.org/10.7554/eLife.95577
