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

Thumu, SCR and Jain, M and Soman, S and Das, S and Verma, V and Nandi, A and Gutmann, DH and Jayaprakash, B and Nair, D and Clement, JP and Marathe, S and Ramanan, N (2024) SRF-deficient astrocytes provide neuroprotection in mouse models of excitotoxicity and neurodegeneration. In: eLife, 13 .

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Abstract

Reactive astrogliosis is a common pathological hallmark of 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 neuro-protection 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 β-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 neuroprotec-tive functions that attenuate neuronal injury in the setting of neurodegenerative diseases. © Thumu et al.

Item Type:	Journal Article
Publication:	eLife
Publisher:	eLife Sciences Publications Ltd
Additional Information:	The copyright for this article belongs to authors.
Keywords:	kainic acid; serum response factor; tamoxifen; serum response factor, adult; Alzheimer disease; amyloid plaque; animal cell; animal experiment; animal model; animal tissue; Article; astrocyte; Barnes maze test; beta amyloid plaque; cell death; cell isolation; cerebral cortical tissue; cerebrospinal fluid; controlled study; corpus striatum; dopaminergic nerve cell; excitotoxicity; experimental design; female; fluorescence intensity; gene expression; gene ontology; hippocampus; immunohistochemistry; knockout mouse; male; mouse; mouse model; nerve cell plasticity; nerve degeneration; nervous system inflammation; neuroprotection; nonhuman; open field test; Parkinson disease; pathway enrichment analysis; phenotype; real time polymerase chain reaction; RNA sequencing; stratum radiatum; synapse; training; transcriptome analysis; transcriptomics; transgenic mouse; TUNEL assay; upregulation; article; astrocytosis; brain function; embryo; gliosis; human
Department/Centre:	Division of Biological Sciences > Centre for Neuroscience
Date Deposited:	15 May 2024 10:45
Last Modified:	15 May 2024 10:45
URI:	https://eprints.iisc.ac.in/id/eprint/84492

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