Tindi Jaafar O, Chávez Andrés E, Cvejic Svetlana, Calvo-Ochoa Erika, Castillo Pablo E, Jordan Bryen A
Dominick P. Purpura Department of Neuroscience.
Dominick P. Purpura Department of Neuroscience, Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York 10461
J Neurosci. 2015 Jun 17;35(24):8986-96. doi: 10.1523/JNEUROSCI.4029-14.2015.
NMDA receptors (NMDARs) are key mediators of glutamatergic transmission and synaptic plasticity, and their dysregulation has been linked to diverse neuropsychiatric and neurodegenerative disorders. While normal NMDAR function requires regulated expression and trafficking of its different subunits, the molecular mechanisms underlying these processes are not fully understood. Here we report that the amyloid precursor protein intracellular domain associated-1 protein (AIDA-1), which associates with NMDARs and is encoded by ANKS1B, a gene recently linked to schizophrenia, regulates synaptic NMDAR subunit composition. Forebrain-specific AIDA-1 conditional knock-out (cKO) mice exhibit reduced GluN2B-mediated and increased GluN2A-mediated synaptic transmission, and biochemical analyses show AIDA-1 cKO mice have low GluN2B and high GluN2A protein levels at isolated hippocampal synaptic junctions compared with controls. These results are corroborated by immunocytochemical and electrophysiological analyses in primary neuronal cultures following acute lentiviral shRNA-mediated knockdown of AIDA-1. Moreover, hippocampal NMDAR-dependent but not metabotropic glutamate receptor-dependent plasticity is impaired in AIDA-1 cKO mice, further supporting a role for AIDA-1 in synaptic NMDAR function. We also demonstrate that AIDA-1 preferentially associates with GluN2B and with the adaptor protein Ca(2+)/calmodulin-dependent serine protein kinase and kinesin KIF17, which regulate the transport of GluN2B-containing NMDARs from the endoplasmic reticulum (ER) to synapses. Consistent with this function, GluN2B accumulates in ER-enriched fractions in AIDA-1 cKO mice. These findings suggest that AIDA-1 regulates NMDAR subunit composition at synapses by facilitating transport of GluN2B from the ER to synapses, which is critical for NMDAR plasticity. Our work provides an explanation for how AIDA-1 dysfunction might contribute to neuropsychiatric conditions, such as schizophrenia.
N-甲基-D-天冬氨酸受体（NMDARs）是谷氨酸能传递和突触可塑性的关键介质，其功能失调与多种神经精神疾病和神经退行性疾病有关。虽然正常的NMDAR功能需要其不同亚基的表达和运输受到调控，但其潜在的分子机制尚未完全明确。在此，我们报告淀粉样前体蛋白胞内结构域相关蛋白1（AIDA-1）与NMDARs相关联，由ANKs1B基因编码，该基因最近被发现与精神分裂症有关，它可调节突触NMDAR亚基的组成。前脑特异性AIDA-1条件性敲除（cKO）小鼠表现出GluN2B介导的突触传递减少，而GluN2A介导的突触传递增加，生化分析表明，与对照组相比，AIDA-1 cKO小鼠在分离出的海马突触连接处GluN2B蛋白水平较低，GluN2A蛋白水平较高。急性慢病毒介导的AIDA-1短发夹RNA（shRNA）敲低后，原代神经元培养物中的免疫细胞化学和电生理分析证实了这些结果。此外，AIDA-1 cKO小鼠海马中依赖NMDAR而非代谢型谷氨酸受体的可塑性受损，进一步支持了AIDA-1在突触NMDAR功能中的作用。我们还证明，AIDA-1优先与GluN2B以及衔接蛋白钙调蛋白依赖性丝氨酸蛋白激酶和驱动蛋白KIF17结合，后者调节含GluN2B的NMDAR从内质网（ER）向突触的运输。与此功能一致，在AIDA-1 cKO小鼠中，GluN2B在内质网丰富的组分中积累。这些发现表明，AIDA-1通过促进GluN2B从内质网向突触的运输来调节突触处NMDAR亚基的组成，这对NMDAR可塑性至关重要。我们的研究为AIDA-1功能障碍可能导致精神分裂症等神经精神疾病提供了解释。
