Shatillo Artem, Salo Raimo A, Giniatullin Rashid, Gröhn Olli H
Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, Kuopio 70700, Finland.
Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, Kuopio 70700, Finland; Lab of Neurobiology, Kazan Federal University, 18 Kremlyovskaya St., Kazan 420008, Republic of Tatarstan, Russian Federation.
Neuropharmacology. 2015 Jun;93:164-70. doi: 10.1016/j.neuropharm.2015.01.028. Epub 2015 Feb 14.
Cortical spreading depression (CSD) is a phenomenon implicated in migraine with aura and associated with other neurological disorders (e.g. stroke, brain trauma). Current evidence points to the essential role of NMDA receptors in CSD mechanisms. However, the roles of multiple subunits of NMDA receptors expressed in neurons, glia and blood vessels in vivo, are little explored. Using BOLD fMRI of urethane anesthetized rats as an integrative CSD readout, we tested the involvement of different NMDA receptor subtypes in CSD induction and propagation. Rats were treated with a non-selective NMDA blocker (MK-801), NR2B antagonist (ifenprodil) or a NR2A selective antagonist (TCN-201). CSD was induced during fMRI scanning by application of KCl onto the cerebral cortex and fMRI data were collected by 9.4 T MRI. The non-specific NMDA antagonist MK-801 completely blocked CSD, which was not observed in the NR2A group where TCN-201 did not alter the CSD features. Unexpectedly, the NR2B specific antagonist ifenprodil largely promoted the initial negative phase of the BOLD CSD response, likely due to altered neurovascular coupling. Our data suggest key roles and differential involvement of NMDA receptor subtypes in CSD generation and propagation, highlighting an important role for the NR2B subtype.
皮质扩散性抑制（CSD）是一种与偏头痛伴先兆有关的现象，并与其他神经系统疾病（如中风、脑外伤）相关。目前的证据表明N-甲基-D-天冬氨酸（NMDA）受体在CSD机制中起关键作用。然而，体内神经元、胶质细胞和血管中表达的NMDA受体多个亚基的作用鲜有研究。我们以氨基甲酸乙酯麻醉大鼠的血氧水平依赖性功能磁共振成像（BOLD fMRI）作为综合的CSD读数，测试了不同NMDA受体亚型在CSD诱导和传播中的作用。给大鼠注射非选择性NMDA阻滞剂（MK-801）、NR2B拮抗剂（ifenprodil）或NR2A选择性拮抗剂（TCN-201）。在功能磁共振成像扫描期间，通过将氯化钾应用于大脑皮层来诱导CSD，并通过9.4T磁共振成像收集功能磁共振成像数据。非特异性NMDA拮抗剂MK-801完全阻断了CSD，而在NR2A组中未观察到这种情况，其中TCN-201并未改变CSD特征。出乎意料的是，NR2B特异性拮抗剂ifenprodil在很大程度上促进了BOLD CSD反应的初始负相，这可能是由于神经血管耦合改变所致。我们的数据表明NMDA受体亚型在CSD产生和传播中起关键作用且涉及方式不同，突出了NR2B亚型的重要作用。
