Ng David, Pitcher Graham M, Szilard Rachel K, Sertié Andréa, Kanisek Marijana, Clapcote Steven J, Lipina Tatiana, Kalia Lorraine V, Joo Daisy, McKerlie Colin, Cortez Miguel, Roder John C, Salter Michael W, McInnes Roderick R
Program in Developmental Biology, The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
PLoS Biol. 2009 Feb 24;7(2):e41. doi: 10.1371/journal.pbio.1000041.
The N-methyl-D-aspartate receptor (NMDAR), a major excitatory ligand-gated ion channel in the central nervous system (CNS), is a principal mediator of synaptic plasticity. Here we report that neuropilin tolloid-like 1 (Neto1), a complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing transmembrane protein, is a novel component of the NMDAR complex critical for maintaining the abundance of NR2A-containing NMDARs in the postsynaptic density. Neto1-null mice have depressed long-term potentiation (LTP) at Schaffer collateral-CA1 synapses, with the subunit dependency of LTP induction switching from the normal predominance of NR2A- to NR2B-NMDARs. NMDAR-dependent spatial learning and memory is depressed in Neto1-null mice, indicating that Neto1 regulates NMDA receptor-dependent synaptic plasticity and cognition. Remarkably, we also found that the deficits in LTP, learning, and memory in Neto1-null mice were rescued by the ampakine CX546 at doses without effect in wild-type. Together, our results establish the principle that auxiliary proteins are required for the normal abundance of NMDAR subunits at synapses, and demonstrate that an inherited learning defect can be rescued pharmacologically, a finding with therapeutic implications for humans.
N-甲基-D-天冬氨酸受体（NMDAR）是中枢神经系统（CNS）中主要的兴奋性配体门控离子通道，是突触可塑性的主要介导者。在此我们报告，神经纤毛蛋白类 tolloid 样蛋白 1（Neto1），一种含补体 C1r/C1s、Uegf、Bmp1（CUB）结构域的跨膜蛋白，是 NMDAR 复合物的一个新组分，对维持突触后致密物中含 NR2A 的 NMDAR 的丰度至关重要。Neto1 基因敲除小鼠在 Schaffer 侧支 - CA1 突触处的长时程增强（LTP）受到抑制，LTP 诱导的亚基依赖性从正常情况下 NR2A 占主导转变为 NR2B - NMDARs 占主导。Neto1 基因敲除小鼠中 NMDAR 依赖的空间学习和记忆受到抑制，表明 Neto1 调节 NMDA 受体依赖的突触可塑性和认知。值得注意的是，我们还发现，安帕金 CX546 能挽救 Neto1 基因敲除小鼠在 LTP、学习和记忆方面的缺陷，且所用剂量对野生型小鼠无影响。总之，我们的结果确立了这样一个原则，即辅助蛋白对于突触处 NMDAR 亚基的正常丰度是必需的，并证明一种遗传性学习缺陷可以通过药物挽救，这一发现对人类具有治疗意义。
