Role NR1/2C and NR1/2D NMDA Receptors in Cortex Function and Memantine Action

描述(申请人提供)：大脑中的大多数兴奋性突触兴奋是由谷氨酸受体介导的。NMDAR是一种由N-甲基-D-天冬氨酸特异性激活的谷氨酸受体亚型，表达于 几乎所有哺乳动物的中枢神经元。NMDAR表现出高的钙离子渗透性和电压依赖性 通道被镁离子阻断，这些特性使它们在突触可塑性和记忆中发挥核心作用。 NMDAR还广泛参与神经系统功能障碍，并与许多神经性疾病有关。 系统疾病，包括阿尔茨海默病(AD)、亨廷顿病、精神分裂症、癫痫和 抑郁症。NMDAR通常由两种亚基组成，即NR1和NR2；有四个NR2 由单独的基因(NR2A-NR2D)编码的亚基，当与NR1结合时，定义了四个主要的 NMDAR亚型(NR1/2A？NR1/2D)。NR1/2A和NR1/2B NMDAR亚型的功能，它们是 在成体皮质中大量表达，已被广泛研究。NR1/2C的功能和 NR1/2D NMDAR亚型，在成人皮质中也有表达(特别是NR1/2D)，尽管表达水平较低 与其他NMDAR亚型相比，水平更不清楚。最近的数据表明，NR1/2C 和/或NR1/2D NMDAR在广泛使用的AD药物的临床应用中发挥着特别重要的作用 美金刚，这是NMDARs的拮抗剂。令人惊讶的是，美金刚，一种减慢速度的药物 阿尔茨海默病患者的认知能力下降，会通过抑制NMDAR发挥作用，NMDAR对记忆至关重要。这个 美金刚的矛盾治疗作用被认为是选择性抑制NR1/2C的结果 NR1/2D受体亚型定位于皮质中间神经元，导致皮质去抑制。这个 NR1/2C和/或NR1/2D NMDAR参与抑制神经元的激活也可能具有特殊意义 对精神分裂症动物模型的意义。这个应用程序的广泛目标是揭示 NR1/2C和NR1/2D NMDARs在皮质中的作用，并提高对作用机制的理解 关于美金刚的。这些目标将通过确定：皮质中的神经元亚型 NR1/2C和/或NR1/2D NMDAR的表达；它们的突触与突触外位置；受体是否 促进紧张性谷氨酸电流；美金刚对几种 皮质中的神经元亚型；NR2D亚单位基因缺失如何影响神经元中的NMDAR反应 以及NR2D亚基基因缺失对美金刚行为效应的影响。 为了实现这些目标，我们将对野生型和突变型啮齿动物应用一种强大的 方法，包括来自脑片的电生理记录，新的受体识别 药理学工具和动物行为分析。拟议的研究将提供基本的 关于皮质NMDAR的信息，对神经系统功能和功能障碍具有广泛的影响，并将 有助于解释一种广泛使用的AD药物的治疗机制。

DESCRIPTION (provided by applicant): Most excitatory synaptic excitation in the brain is mediated by glutamate receptors. NMDA receptors (NMDARs), a glutamate receptor subtype specifically activated by N-methyl-D-aspartate, are expressed on almost all mammalian central neurons. NMDARs exhibit high Ca2+ permeability and voltage-dependent channel block by Mg2+, characteristics that allow them to play central roles in synaptic plasticity and memory. NMDARs also are broadly involved in nervous system dysfunction, and have been implicated in many nervous system diseases including Alzheimer's disease (AD), Huntington's disease, schizophrenia, epilepsy, and depression. NMDARs are usually composed of two types of subunits, NR1 and NR2; there are four NR2 subunits encoded by separate genes (NR2A-NR2D), which, when combined with NR1, define four major NMDAR subtypes (NR1/2A ¿ NR1/2D). The function of the NR1/2A and NR1/2B NMDAR subtypes, which are heavily expressed in adult cortex, have been extensively investigated. The function of the NR1/2C and NR1/2D NMDAR subtypes, which also are expressed in adult cortex (especially NR1/2D), although at lower levels than the other NMDAR subtypes, are less well understood. Recent data suggest that the NR1/2C and/or NR1/2D NMDARs play an especially important role in the clinical utility of the widely-used AD drug memantine, which is an antagonist of NMDARs. It appears surprising that memantine, a drug that slows cognitive decline in AD patients, would act by inhibiting NMDARs, which are essential for memory. The paradoxical therapeutic effects of memantine have been proposed to result from selective inhibition of NR1/2C and NR1/2D receptor subtypes located on cortical interneurons, resulting in cortical disinhibition. The involvement of NR1/2C and/or NR1/2D NMDARs in activation of inhibitory neurons also may be of special significance to animal models of schizophrenia. The broad objectives of this application are to uncover the roles of NR1/2C and NR1/2D NMDARs in the cortex, and to improve understanding of the mechanism of action of memantine. These objectives will be accomplished by determining: the neuronal subtypes in cortex that express NR1/2C and/or NR1/2D NMDARs; their synaptic versus extrasynaptic location; whether the receptors contribute to tonically active glutamate currents; the effects of memantine on NMDAR responses of several neuronal subtypes in cortex; how genetic deletion of the NR2D subunit affects NMDAR responses in neuronal subtypes in cortex; and the influence of NR2D subunit genetic deletion on the behavioral effects of memantine. To achieve these goals we will apply, to both wild-type and mutant rodents, a powerful combination of approaches, including electrophysiological recordings from brain slices, receptor identification with new pharmacological tools, and analysis of animal behavior. The proposed research will provide fundamental information on cortical NMDARs with broad implications for nervous system function and dysfunction, and will help explain the therapeutic mechanism of a widely used AD drug.