ArticleMolecular neurodegeneration2023
The Q/R editing site of AMPA receptor GluA2 subunit acts as an epigenetic switch regulating dendritic spines, neurodegeneration and cognitive deficits in Alzheimer's disease.
Article in Molecular neurodegeneration, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 33 citations in OpenAlex.
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- Activation of Kv7.3 channels in mPFC engram neurons suppresses methamphetamine memory retrieval by reducing excitability and glutamate release in the mPFC-NAc circuit.Cellular and molecular life sciences : CMLS · 2026Article
- Global hotspots and trends in AMPA receptor research (2000-2025): a bibliometric and visualization analysis.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- From Atoms to Neuronal Spikes: A Multiscale Simulation Framework.Journal of chemical theory and computation · 2026Review
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- High Conservation of Translation-Enabling RNA Editing Sites in Hyper-editing Ferns Implies They Are Not Selectively Neutral.Molecular biology and evolution · 2025Article
- ADARs: pleiotropy in function, versatility in application.Nucleic acids research · 2025Review
- RNA dysregulation in neurodegenerative diseases.The EMBO journal · 2025Review
- AMPA Receptors in Synaptic Plasticity, Memory Function, and Brain Diseases.Cellular and molecular neurobiology · 2025Review
- Electrophysiology-based screening identifies neuronal HtrA serine peptidase 2 (HTRA2) as a synaptic plasticity regulator participating in tauopathy.Translational psychiatry · 2025Article
- REDIportal: toward an integrated view of the A-to-I editing.Nucleic acids research · 2025Article
- The Flipons, Infections, and Amyloids that Foreshadow the Fading Memories of Alzheimer's Disease.Neuroscience insights · 2025Review
- AMPA receptors in the evolving synapse: structure, function, and disease implications.Frontiers in synaptic neuroscience · 2025Review
- Alzheimer's therapeutic development: shifting neurodegeneration to neuroregeneration.Trends in pharmacological sciences · 2024Review
- Toward the development of a sporadic model of Alzheimer's disease: comparing pathologies between humanized APP and the familial J20 mouse models.Frontiers in aging neuroscience · 2024Article
- Quantification of AMPA receptor subunits and RNA editing-related proteins in the J20 mouse model of Alzheimer's disease by capillary western blotting.Frontiers in molecular neuroscience · 2023Article
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Authors and funding
16 authors at 11 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundRNA editing at the Q/R site of GluA2 occurs with ~99% efficiency in the healthy brain, so that the majority of AMPARs contain GluA2(R) instead of the exonically encoded GluA2(Q). Reduced Q/R site editing infcreases AMPA receptor calcium permeability and leads to dendritic spine loss, neurodegeneration, seizures and learning impairments. Furthermore, GluA2 Q/R site editing is impaired in Alzheimer's disease (AD), raising the possibility that unedited GluA2(Q)-containing AMPARs contribute to synapse loss and neurodegeneration in AD. If true, then inhibiting expression of unedited GluA2(Q), while maintaining expression of GluA2(R), may be a novel strategy of preventing synapse loss and neurodegeneration in AD.
methodsWe engineered mice with the 'edited' arginine codon (CGG) in place of the unedited glutamine codon (CAG) at position 607 of the Gria2 gene. We crossbred this line with the J20 mouse model of AD and conducted anatomical, electrophysiological and behavioural assays to determine the impact of eliminating unedited GluA2(Q) expression on AD-related phenotypes.
resultsEliminating unedited GluA2(Q) expression in AD mice prevented dendritic spine loss and hippocampal CA1 neurodegeneration as well as improved working and reference memory in the radial arm maze. These phenotypes were improved independently of Aβ pathology and ongoing seizure susceptibility. Surprisingly, our data also revealed increased spine density in non-AD mice with exonically encoded GluA2(R) as compared to their wild-type littermates, suggesting an unexpected and previously unknown role for unedited GluA2(Q) in regulating dendritic spines.
conclusionThe Q/R editing site of the AMPA receptor subunit GluA2 may act as an epigenetic switch that regulates dendritic spines, neurodegeneration and memory deficits in AD.
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