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

Molecular Brain

Raphael Zinn¹  Bryce Vissel¹  Lyndsey M. Konen¹  Gary P. Morris¹  Luke T. Milham¹  Amanda L. Wright²  Patrick W. Seow³  Benjamin K. Lau³  Christopher W. Vaughan³  Gordon A. Royle⁴ 

[1] Centre for Neuroscience and Regenerative Medicine (CNRM), Faculty of Science, University of Technology Sydney;Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Macquarie University;Kolling Institute of Medical Research, Royal North Shore Hospital, The University of Sydney;Middlemore Hospital, Counties Manukau DHB, Otahuhu;

关键词: GluA2;    AMPA receptors;    RNA editing;    Hippocampus;    Seizures;    Neurodegeneration;   

DOI  :  10.1186/s13041-020-0545-1

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown