Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning.
Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning.
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DOI：
10.1371/journal.pbio.1000041
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发表时间：
2009-02-24
期刊：
影响因子：
9.8
通讯作者：
McInnes RR
中科院分区：
文献类型：
--
作者：
Ng D;Pitcher GM;Szilard RK;Sertié A;Kanisek M;Clapcote SJ;Lipina T;Kalia LV;Joo D;McKerlie C;Cortez M;Roder JC;Salter MW;McInnes RR
N-甲基-D-天冬氨酸受体（NMDAR）是中枢神经系统（CNS）的一种主要兴奋性配体门控离子通道，是突触可塑性的主要介质。在这里，我们报告，neuropilin tolloid-like 1（Neto 1），补体C1 r/C1 s，Uegf，Bmp 1（CUB）域的跨膜蛋白，是一个新的组件的NMDAR复合物的关键维持丰富的NR 2A-含有NMDAR的突触后密度。Neto 1基因敲除小鼠Schaffer侧支-CA 1突触的长时程增强（LTP）受到抑制，LTP诱导的亚基依赖性从NR 2A-NMDAR的正常优势切换到NR 2B-NMDAR。NMDAR依赖的空间学习和记忆在Neto 1基因敲除小鼠中被抑制，表明Neto 1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，Neto 1基因敲除小鼠的LTP、学习和记忆缺陷在野生型小鼠中没有效果的剂量下被安巴金CX 546挽救。总之，我们的研究结果确立了辅助蛋白是突触处NMDAR亚基正常丰度所需的原则，并证明了遗传性学习缺陷可以被挽救，这一发现对人类具有治疗意义。大脑中信息处理的基本单位是突触，这是大脑中众多单个神经元之间高度专门化的通信场所。每个突触的通讯强度会随着神经元的活动而变化，这一过程被称为突触可塑性，使得神经元网络能够适应和学习。突触可塑性如何发生是神经生物学中的一个主要问题。突触可塑性的一个中心角色是称为NMDA受体复合物的突触蛋白的组装。在这里，我们发现蛋白Neto 1是NMDA受体复合物的一个组成部分。Neto 1缺陷小鼠突触处NMDA受体数量显著减少，因此，突触可塑性和学习能力受损。通过用一种小分子间接增强Neto 1缺陷小鼠中残余NMDA受体的功能，我们将突触可塑性和学习恢复到正常水平。我们的研究结果确立了这样的原则，即由于NMDA受体功能障碍导致的突触可塑性和学习的遗传异常可以被纠正。我们的发现还表明，与Neto 1共享分子特征（称为CUB结构域）的突触蛋白可能是跨物种突触受体的重要组成部分，因为蠕虫中的几种CUB结构域蛋白也被发现调节突触受体。空间学习和记忆依赖于N-甲基-D-天冬氨酸受体，一种由Neto 1调节的突触离子通道。由于缺乏Neto 1而导致的认知受损可以被挽救，这一发现对人类遗传性学习缺陷的治疗具有重要意义。
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. The fundamental unit for information processing in the brain is the synapse, a highly specialized site of communication between the brain's multitude of individual neurons. The strength of the communication at each synapse changes in response to neuronal activity—a process called synaptic plasticity—allowing networks of neurons to adapt and learn. How synaptic plasticity occurs is a major question in neurobiology. A central player in synaptic plasticity is an assembly of synaptic proteins called the NMDA receptor complex. Here, we discovered that the protein Neto1 is a component of the NMDA receptor complex. Neto1-deficient mice had a dramatic decrease in the number of NMDA receptors at synapses and consequently, synaptic plasticity and learning were impaired. By indirectly enhancing the function of the residual NMDA receptors in Neto1-deficient mice with a small molecule, we restored synaptic plasticity and learning to normal levels. Our findings establish the principle that inherited abnormalities of synaptic plasticity and learning due to NMDA receptor dysfunction can be pharmacologically corrected. Our discoveries also suggest that synaptic proteins that share a molecular signature, called the CUB domain, with Neto1 may be important components of synaptic receptors across species, because several CUB-domain proteins in worms have also been found to regulate synaptic receptors. Spatial learning and memory depend on the N-methyl-D-aspartic acid receptor, a synaptic ion channel regulated by Neto1. Impaired cognition due to the absence of Neto1 can be rescued pharmacologically, a finding with implications for the therapy of inherited learning defects in humans.
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