Abstract：
Alternative splicing of Grin1 exon 5 regulates induction of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses: LTP in mice lacking the GluN1 exon 5-encoded N1 cassette (GluN1a mice) is significantly increased compared with that in mice compulsorily expressing this exon (GluN1b mice). The mechanism underlying this difference is unknown. Here, we report that blocking the non-receptor tyrosine kinase Src prevents induction of LTP in GluN1a mice but not in GluN1b. We find that activating Src enhances pharmacologically isolated synaptic N-methyl-d-aspartate receptor (NMDAR) currents in GluN1a mice but not in GluN1b. Moreover, we observe that Src activation increases the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor component of Schaffer collateral-evoked excitatory post-synaptic potentials in GluN1a mice, but this increase is prevented by blocking NMDARs. We conclude that at these synapses, NMDARs in GluN1a mice are subject to upregulation by Src that mediates induction of LTP, whereas NMDARs in GluN1b mice are not regulated by Src, leading to Src-resistance of LTP. Thus, we have uncovered that a key regulatory mechanism for synaptic potentiation is gated by differential splicing of exon 5 of Grin1. This article is part of a discussion meeting issue \'Long-term potentiation: 50 years on\'.
摘要：
Grin1外显子5的选择性剪接调节Schaffer侧支CA1突触的长时程增强（LTP）的诱导：与强制表达该外显子的小鼠相比，缺乏GluN1外显子5编码的N1盒的小鼠（GluN1a小鼠）的LTP显着增加（GluN1b小鼠）。这种差异的潜在机制是未知的。这里,我们报道,阻断非受体酪氨酸激酶Src阻止GluN1a小鼠中LTP的诱导,但不阻止GluN1b中LTP的诱导.我们发现，激活Src可增强GluN1a小鼠的药理学分离的突触N-甲基-d-天冬氨酸受体（NMDAR）电流，而不是GluN1b。此外，我们观察到Src激活增加了GluN1a小鼠Schaffer侧支诱发兴奋性突触后电位的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体成分，但是通过阻止NMDAR可以防止这种增加。我们得出结论，在这些突触上，GluN1a小鼠中的NMDARs受到Src的上调，介导LTP的诱导，而GluN1b小鼠的NMDARs不受Src调控，导致LTP的Src抗性。因此，我们已经发现，突触增强的关键调节机制是由Grin1外显子5的差异剪接决定的。本文是讨论会议问题“长期增强：50年后”的一部分。
