2. Academic Validation
  3. 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

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

  • Mol Brain. 2020 Feb 27;13(1):27. doi: 10.1186/s13041-020-0545-1.
Lyndsey M Konen 1 2,  Amanda L Wright 3,  Gordon A Royle 4 5,  Gary P Morris 1 2,  Benjamin K Lau 6,  Patrick W Seow 6,  Raphael Zinn 1 2,  Luke T Milham 1 2,  Christopher W Vaughan 6,  Bryce Vissel 7 8
Affiliations

Affiliations

  • 1 Centre for Neuroscience and Regenerative Medicine (CNRM), Faculty of Science, University of Technology Sydney, PO Box 123 Broadway, Sydney, NSW, 2007, Australia.
  • 2 St Vincent's Centre for Applied Medical Research, Sydney, 2011, Australia.
  • 3 Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Macquarie University, Sydney, New South Wales, 2109, Australia.
  • 4 Middlemore Hospital, Counties Manukau DHB, Otahuhu, Auckland, 1062, New Zealand.
  • 5 The University of Auckland, Faculty of Medical and Health Sciences, School of Medicine, Grafton, Auckland, 1023, New Zealand.
  • 6 Kolling Institute of Medical Research, Royal North Shore Hospital, The University of Sydney, Sydney, 2065, Australia.
  • 7 Centre for Neuroscience and Regenerative Medicine (CNRM), Faculty of Science, University of Technology Sydney, PO Box 123 Broadway, Sydney, NSW, 2007, Australia. [email protected].
  • 8 St Vincent's Centre for Applied Medical Research, Sydney, 2011, Australia. [email protected].
PMID: 32102661 DOI: 10.1186/s13041-020-0545-1
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.

Keywords

AMPA receptors; Alzheimer’s disease; GluA2; Hippocampus; Long term potentiation; Neurodegeneration; RNA editing; Seizures; Synapses.

Figures