Control of Long-Term Synaptic Potentiation and Learning by Alternative Splicing of the NMDA Receptor Subunit GluN1.,Cell Reports

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Control of Long-Term Synaptic Potentiation and Learning by Alternative Splicing of the NMDA Receptor Subunit GluN1.
Cell Reports ( IF 7.5 ) Pub Date : 2019-12-24 , DOI: 10.1016/j.celrep.2019.11.087
Ameet S Sengar ₁ , Hongbin Li ₁ , Wenbo Zhang ₁ , Celeste Leung ₂ , Arun K Ramani ₃ , Ner Mu Saw ₂ , Yongqian Wang ₁ , YuShan Tu ₁ , P Joel Ross ₄ , Stephen W Scherer ₅ , James Ellis ₆ , Michael Brudno ₇ , Zhengping Jia ₂ , Michael W Salter ₂

Affiliation

Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Centre for Computational Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Biology Department, University of Prince Edward Island, Charlottetown, PE C1A 4P3, Canada.
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; McLaughlin Centre, University of Toronto, Toronto, ON M5G 0A4, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Centre for Computational Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5T 3A1, Canada.

NMDA receptors (NMDARs) are critical for physiological synaptic plasticity, learning, and memory and for pathological plasticity and neuronal death. The GluN1 subunit is encoded by a single gene, GRIN1, with 8 splice variants, but whether the diversity generated by this splicing has physiological consequences remains enigmatic. Here, we generate mice lacking from the GluN1 exon 5-encoded N1 cassette (GluN1a mice) or compulsorily expressing this exon (GluN1b mice). Despite no differences in basal synaptic transmission, long-term potentiation in the hippocampus is significantly enhanced in GluN1a mice compared with that in GluN1b mice. Furthermore, GluN1a mice learn more quickly and have significantly better spatial memory performance than do GluN1b mice. In addition, in human iPSC-derived neurons in autism spectrum disorder NMDARs show characteristics of N1-lacking GluN1. Our findings indicate that alternative splicing of GluN1 is a mechanism for controlling physiological long-lasting synaptic potentiation, learning, and memory.

中文翻译：

通过替代剪接的NMDA受体亚基GluN1的长期突触增强和学习的控制。

NMDA受体（NMDAR）对于生理突触可塑性，学习和记忆以及病理可塑性和神经元死亡至关重要。GluN1亚基由具有8个剪接变体的单个基因GRIN1编码，但是这种剪接产生的多样性是否具有生理后果仍然是个谜。在这里，我们生成的小鼠缺少GluN1外显子5编码的N1盒（GluN1a小鼠）或强制表达该外显子的小鼠（GluN1b小鼠）。尽管基础突触传递没有差异，但与GluN1b小鼠相比，GluN1a小鼠海马的长期增强作用显着增强。此外，与GluN1b小鼠相比，GluN1a小鼠学习更快，并且具有明显更好的空间记忆性能。此外，自闭症谱系障碍的人iPSC衍生神经元中的NMDARs表现出缺乏N1的GluN1的特征。我们的发现表明，GluN1的选择性剪接是一种控制生理上持久的突触增强，学习和记忆的机制。

更新日期：2019-12-25

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