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.
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)
SRF-deficient astrocytes provide neuroprotection in mouse models of excitotoxicity and neurodegeneration
eLife 13:e95577.
https://doi.org/10.7554/eLife.95577
Further reading
-
- Neuroscience
Sensory experience during developmental critical periods has lifelong consequences for circuit function and behavior, but the molecular and cellular mechanisms through which experience causes these changes are not well understood. The Drosophila antennal lobe houses synapses between olfactory sensory neurons (OSNs) and downstream projection neurons (PNs) in stereotyped glomeruli. Many glomeruli exhibit structural plasticity in response to early-life odor exposure, indicating a general sensitivity of the fly olfactory circuitry to early sensory experience. We recently found that glia shape antennal lobe development in young adults, leading us to ask if glia also drive experience-dependent plasticity during this period. Here, we define a critical period for structural and functional plasticity of OSN-PN synapses in the ethyl butyrate (EB)-sensitive glomerulus VM7. EB exposure for the first 2 days post-eclosion drives large-scale reductions in glomerular volume, presynapse number, and post- synaptic activity. Crucially, pruning during the critical period has long-term consequences for circuit function since both OSN-PN synapse number and spontaneous activity of PNs remain persistently decreased following early-life odor exposure. The highly conserved engulfment receptor Draper is required for this critical period plasticity as ensheathing glia upregulate Draper, invade the VM7 glomerulus, and phagocytose OSN presynaptic terminals in response to critical-period EB exposure. Loss of Draper fully suppresses the morphological and physiological consequences of critical period odor exposure, arguing that phagocytic glia engulf intact synaptic terminals. These data demonstrate experience-dependent pruning of synapses and argue that Drosophila olfactory circuitry is a powerful model for defining the function of glia in critical period plasticity.
