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A new mouse line with reduced GluA2 Q/R site RNA editing exhibits loss of dendritic spines, hippocampal CA1-neuron loss, learning and memory impairments and NMDA receptor-independent seizure vulnerability

Authors
  • Konen, Lyndsey M.1, 2
  • Wright, Amanda L.3
  • Royle, Gordon A.4, 5
  • Morris, Gary P.1, 2
  • Lau, Benjamin K.6
  • Seow, Patrick W.6
  • Zinn, Raphael1, 2
  • Milham, Luke T.1, 2
  • Vaughan, Christopher W.6
  • Vissel, Bryce1, 2
  • 1 University of Technology Sydney, Sydney, NSW, 2007, Australia , Sydney (Australia)
  • 2 St Vincent’s Centre for Applied Medical Research, Sydney, 2011, Australia , Sydney (Australia)
  • 3 Macquarie University, Sydney, New South Wales, 2109, Australia , Sydney (Australia)
  • 4 Counties Manukau DHB, Otahuhu, Auckland, 1062, New Zealand , Auckland (New Zealand)
  • 5 The University of Auckland, Faculty of Medical and Health Sciences, School of Medicine, Grafton, Auckland, 1023, New Zealand , Auckland (New Zealand)
  • 6 The University of Sydney, Sydney, 2065, Australia , Sydney (Australia)
Type
Published Article
Journal
Molecular Brain
Publisher
BioMed Central
Publication Date
Feb 27, 2020
Volume
13
Issue
1
Identifiers
DOI: 10.1186/s13041-020-0545-1
Source
Springer Nature
Keywords
License
Green

Abstract

Calcium (Ca2+)-permeable AMPA receptors may, in certain circumstances, contribute to normal synaptic plasticity or to neurodegeneration. AMPA receptors are Ca2+-permeable if they lack the GluA2 subunit or if GluA2 is unedited at a single nucleic acid, known as the Q/R site. In this study, we examined mice engineered with a point mutation in the intronic editing complementary sequence (ECS) of the GluA2 gene, Gria2. Mice heterozygous for the ECS mutation (named GluA2+/ECS(G)) had a ~ 20% reduction in GluA2 RNA editing at the Q/R site. We conducted an initial phenotypic analysis of these mice, finding altered current-voltage relations (confirming expression of Ca2+-permeable AMPA receptors at the synapse). Anatomically, we observed a loss of hippocampal CA1 neurons, altered dendritic morphology and reductions in CA1 pyramidal cell spine density. Behaviourally, GluA2+/ECS(G) mice exhibited reduced motor coordination, and learning and memory impairments. Notably, the mice also exhibited both NMDA receptor-independent long-term potentiation (LTP) and vulnerability to NMDA receptor-independent seizures. These NMDA receptor-independent seizures were rescued by the Ca2+-permeable AMPA receptor antagonist IEM-1460. In summary, unedited GluA2(Q) may have the potential to drive NMDA receptor-independent processes in brain function and disease. Our study provides an initial characterisation of a new mouse model for studying the role of unedited GluA2(Q) in synaptic and dendritic spine plasticity in disorders where unedited GluA2(Q), synapse loss, neurodegeneration, behavioural impairments and/or seizures are observed, such as ischemia, seizures and epilepsy, Huntington’s disease, amyotrophic lateral sclerosis, astrocytoma, cocaine seeking behaviour and Alzheimer’s disease.

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