Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, Magdeburg, Germany.
Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.
Sci Rep. 2017 Aug 4;7(1):7273. doi: 10.1038/s41598-017-07839-9.
The cell adhesion molecule neuroplastin (Np) is a novel candidate to influence human intelligence. Np-deficient mice display complex cognitive deficits and reduced levels of Plasma Membrane Ca ATPases (PMCAs), an essential regulator of the intracellular Ca concentration ([iCa]) and neuronal activity. We show abundant expression and conserved cellular and molecular features of Np in glutamatergic neurons in human hippocampal-cortical pathways as characterized for the rodent brain. In Nptn mice, glutamatergic neuron-selective Np ablation resulted in behavioral deficits indicating hippocampal, striatal, and sensorimotor dysfunction paralleled by highly altered activities in hippocampal CA1 area, sensorimotor cortex layers I-III/IV, and the striatal sensorimotor domain detected by single-photon emission computed tomography. Altered hippocampal and cortical activities correlated with reduction of distinct PMCA paralogs in Nptn mice and increased [iCa] in cultured mutant neurons. Human and rodent Np enhanced the post-transcriptional expression of and co-localized with PMCA paralogs in the plasma membrane of transfected cells. Our results indicate Np as essential for PMCA expression in glutamatergic neurons allowing proper [iCa] regulation and normal circuit activity. Neuron-type-specific Np ablation empowers the investigation of circuit-coded learning and memory and identification of causal mechanisms leading to cognitive deterioration.
神经细胞黏附分子神经钙黏蛋白（Np）是影响人类智力的一个新的候选因子。Np 缺陷型小鼠表现出复杂的认知缺陷和血浆膜 Ca ATP 酶（PMCAs）水平降低，后者是细胞内 Ca 浓度（[iCa]）和神经元活动的重要调节剂。我们在人类海马-皮质通路的谷氨酸能神经元中显示出丰富的 Np 表达，并具有与啮齿动物大脑相似的保守细胞和分子特征。在 Nptn 小鼠中，谷氨酸能神经元选择性的 Np 缺失导致行为缺陷，表明海马、纹状体和感觉运动功能障碍，同时伴有海马 CA1 区、感觉运动皮层 I-III/IV 层和纹状体感觉运动区的高度异常活动，这些活动通过单光子发射计算机断层扫描检测到。海马和皮质活动的改变与 Nptn 小鼠中特定 PMCA 同系物的减少以及培养的突变神经元中 [iCa] 的增加相关。人和啮齿动物的 Np 增强了转染细胞质膜中 PMCA 同系物的转录后表达，并与 PMCA 同系物共定位。我们的结果表明 Np 是谷氨酸能神经元中 PMCA 表达所必需的，允许适当的 [iCa] 调节和正常的回路活动。神经元类型特异性的 Np 缺失能够增强对与电路编码的学习和记忆相关的回路的研究，并识别导致认知恶化的因果机制。
