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

Amanda L Wright; Lyndsey M Konen; Bruce G Mockett; Gary P Morris; Anurag Singh; Lisseth Estefania Burbano; Luke Milham; Monica Hoang; Raphael Zinn; Rose Chesworth; Richard P Tan; Gordon A Royle; Ian Clark; Steven Petrou; Wickliffe C Abraham; Bryce Vissel

doi:10.1186/s13024-023-00632-5

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

Mol Neurodegener. 2023 Sep 28;18(1):65. doi: 10.1186/s13024-023-00632-5.

Authors

Amanda L Wright^#^{1

2}, Lyndsey M Konen^#³, Bruce G Mockett^#⁴, Gary P Morris^#^{3

5}, Anurag Singh^#⁴, Lisseth Estefania Burbano^{6

7}, Luke Milham^{1

3}, Monica Hoang⁸, Raphael Zinn³, Rose Chesworth⁹, Richard P Tan^{10

11}, Gordon A Royle^{12

13}, Ian Clark¹⁴, Steven Petrou^{6

7}, Wickliffe C Abraham⁴, Bryce Vissel^{15

16}

Affiliations

¹ St Vincent's Clinical School, St Vincent's Hospital Sydney, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, 2010, Australia.
² School of Rural Medicine, Charles Sturt University, Orange, NSW, 2800, Australia.
³ Centre for Neuroscience and Regenerative Medicine, St Vincent's Centre for Applied Medical Research, St Vincent's Hospital Sydney, Darlinghurst, NSW, 2010, Australia.
⁴ Department of Psychology, Brain Health Research Centre, Brain Research New Zealand, University of Otago, Box 56, Dunedin, 9054, New Zealand.
⁵ Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, TAS, 7005, Australia.
⁶ Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3010, Australia.
⁷ Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia.
⁸ School of Pharmacy, University of Waterloo, Kitchener, ON, N2G 1C5, Canada.
⁹ School of Medicine, Western Sydney University, Campbelltown, NSW, 2560, Australia.
¹⁰ Chronic Diseases, School of Medical Sciences, Faculty of Health and Medicine, University of Sydney, Sydney, NSW, 2050, Australia.
¹¹ Charles Perkins Centre, University of Sydney, Sydney, NSW, 2006, Australia.
¹² Middlemore Hospital, Counties Manukau DHB, Otahuhu, Auckland, 1062, New Zealand.
¹³ Faculty of Medical and Health Sciences, University of Auckland, Grafton, Auckland, 1023, New Zealand.
¹⁴ Research School of Biology, Australian National University, Canberra, ACT, 0200, Australia.
¹⁵ St Vincent's Clinical School, St Vincent's Hospital Sydney, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, 2010, Australia. BryceVissel@gmail.com.
¹⁶ Centre for Neuroscience and Regenerative Medicine, St Vincent's Centre for Applied Medical Research, St Vincent's Hospital Sydney, Darlinghurst, NSW, 2010, Australia. BryceVissel@gmail.com.

^# Contributed equally.

Abstract

Background: RNA 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.

Methods: We 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.

Results: Eliminating 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.

Conclusion: The 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.

Keywords: AMPAR; Alzheimer’s disease; GluA2; Neurodegeneration; RNA editing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / genetics
Animals
Cognition
Dendritic Spines*
Epigenesis, Genetic
Mice
Receptors, AMPA

Substances

Receptors, AMPA