Interneuronal NMDA receptors regulate long-term depression and motor learning in the cerebellum
Interneuronal NMDA receptors regulate long-term depression and motor learning in the cerebellum
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DOI：
10.1113/jp276794
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发表时间：
2019-02-01
影响因子：
5.5
通讯作者：
Yuzaki, Michisuke
中科院分区：
文献类型：
--
作者：
Kono, Maya;Kakegawa, Wataru;Yuzaki, Michisuke
长时程增强（LTP）和抑郁（LTD）是学习记忆的细胞突触可塑性模型，在不同脑区受到N-甲基-d-天冬氨酸受体（NMDARs）的重要调节。在小脑中，平行纤维（PF）-浦肯野细胞（PC）突触处的LTP和LTD被认为介导某些形式的运动学习。然而，虽然NMDAR对于LTD体外是必不可少的，但它们的细胞定位仍然存在争议。此外，NMDARs是否以及如何介导体内运动学习仍不清楚。在这里，我们研究了NMDARs在颗粒细胞（GC），PC和分子层中间神经元（MLI）LTD/LTP和运动学习的贡献，通过产生GC-，PC-和MLI/PC-特异性敲除Grin 1，一个基因编码的NMDARs的一个强制性GluN 1亚基。虽然在GC和PC特异性Grin 1（分别为GC-Grin 1和PC-Grin 1）条件性敲除（cKO）小鼠中，在PF-PC突触处诱导了稳健的LTD和LTP，但在MLI/PC特异性Grin 1（MLI/PC-Grin 1）cKO小鼠中仅LTD受损。二乙胺一氧化氮（NO）钠，一个有效的NO供体，应用于小脑切片恢复LTD在MLI/PC-Grin 1 cKO小鼠，这表明NO可能是下游的NMDAR。此外，水平视动反应（hOKR）的适应，小脑运动学习任务，通常观察到GC-Grin 1 cKO和PC-Grin 1 cKO小鼠，但在MLI/PC-Grin 1 cKO小鼠。这些结果表明，MLI中表达的NMDAR，而不是在PC或GC中，在LTD体外和体内运动学习中发挥重要作用。
Long-term potentiation (LTP) and depression (LTD), which serve as cellular synaptic plasticity models for learning and memory, are crucially regulated by N-methyl-d-aspartate receptors (NMDARs) in various brain regions. In the cerebellum, LTP and LTD at parallel fibre (PF)-Purkinje cell (PC) synapses are thought to mediate certain forms of motor learning. However, while NMDARs are essential for LTD invitro, their cellular localization remains controversial. In addition, whether and how NMDARs mediate motor learning invivo remains unclear. Here, we examined the contribution of NMDARs expressed in granule cells (GCs), PCs and molecular-layer interneurons (MLIs) to LTD/LTP and motor learning by generating GC-, PC- and MLI/PC-specific knockouts of Grin1, a gene encoding an obligatory GluN1 subunit of NMDARs. While robust LTD and LTP were induced at PF-PC synapses in GC- and PC-specific Grin1 (GC-Grin1 and PC-Grin1, respectively) conditional knockout (cKO) mice, only LTD was impaired in MLI/PC-specific Grin1 (MLI/PC-Grin1) cKO mice. Application of diethylamine nitric oxide (NO) sodium, a potent NO donor, to the cerebellar slices restored LTD in MLI/PC-Grin1 cKO mice, suggesting that NO is probably downstream to NMDARs. Furthermore, the adaptation of horizontal optokinetic responses (hOKR), a cerebellar motor learning task, was normally observed in GC-Grin1 cKO and PC-Grin1 cKO mice, but not in MLI/PC-Grin1 cKO mice. These results indicate that it is the NMDARs expressed in MLIs, but not in PCs or GCs, that play important roles in LTD invitro and motor learning invivo.