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.

中文翻译：

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具有减少的GluA2 Q / R位点RNA编辑的新小鼠系表现出树突棘丧失，海马CA1-神经元丧失，学习和记忆障碍以及NMDA受体非依赖性癫痫发作。

钙（Ca2 +）渗透性AMPA受体在某些情况下可能有助于正常的突触可塑性或神经退行性变。如果AMPA受体缺少GluA2亚基，或者如果GluA2在单个核酸（称为Q / R位点）上未编辑，则它们可渗透Ca2 +。在这项研究中，我们检查了在GluA2基因Gria2的内含子编辑互补序列（ECS）中点突变的工程小鼠。ECS突变的杂合小鼠（名为GluA2 + / ECS（G））在Q / R位点的GluA2 RNA编辑降低了20％。我们对这些小鼠进行了初步的表型分析，发现其电流-电压关系发生了改变（确认突触中可渗透Ca2 +的AMPA受体的表达）。解剖上，我们观察到海马CA1神经元的丢失，树突形态的改变以及CA1锥体细胞脊柱密度的降低。行为上，GluA2 + / ECS（G）小鼠表现出降低的运动协调性，以及学习和记忆障碍。值得注意的是，小鼠还表现出不依赖于NMDA受体的长期增强作用（LTP）和不依赖于NMDA受体的癫痫发作的脆弱性。这些不依赖NMDA受体的癫痫发作可通过可渗透Ca2 +的AMPA受体拮抗剂IEM-1460挽救。总而言之，未经编辑的GluA2（Q）可能具有驱动NMDA受体非依赖性过程在大脑功能和疾病中的潜能。我们的研究为研究未编辑的GluA2（Q）在未编辑的GluA2（Q），突触丢失，神经退行性病变，行为障碍和/或癫痫发作的疾病中研究未编辑的GluA2（Q）在突触和树突棘可塑性中的作用提供了初步的表征。例如缺血，癫痫和癫痫，亨廷顿舞蹈病，