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

描述（由申请人提供）：大脑中的大多数兴奋性突触兴奋由谷氨酸受体介导。NMDA受体（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 几乎所有的哺乳动物中枢神经元。NMDAR表现出高Ca 2+渗透性和电压依赖性 通道阻滞的Mg 2+，特点，使他们发挥核心作用，突触可塑性和记忆。 NMDAR还广泛涉及神经系统功能障碍，并且已经涉及许多神经系统疾病。 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 萧条NMDAR通常由两种类型的亚基组成，NR 1和NR 2; 由不同基因编码的亚基（NR 2A-NR 2D），当与NR 1结合时， NMDAR亚型（NR 1/2A <$NR1/2D）。NR 1/2A和NR 1/2B NMDAR亚型的功能， 在成人皮质中大量表达，已经被广泛研究。NR 1/2C的功能和 NR 1/2D NMDAR亚型也在成人皮质中表达（尤其是NR 1/2D），尽管在较低水平， 与其他NMDAR亚型相比，NMDAR的水平还不太清楚。最近的数据表明，NR 1/2C 和/或NR 1/2D NMDAR在广泛使用的AD药物的临床应用中起着特别重要的作用 美金刚，其是NMDAR的拮抗剂。令人惊讶的是，美金刚，一种减缓 在AD患者中的认知下降将通过抑制NMDAR起作用，NMDAR对于记忆是必需的。的 已经提出美金刚的矛盾的治疗效果是由于选择性抑制NR 1/2C NR 1/2D受体亚型定位于皮层中间神经元，导致皮层去抑制。的 NR 1/2C和/或NR 1/2D NMDAR参与抑制性神经元的激活也可能是一种特殊的 精神分裂症动物模型的意义。此应用程序的主要目标是揭示 NR 1/2C和NR 1/2D NMDARs在皮质中的作用，并提高对作用机制的理解 美金刚。这些目标将通过确定：皮质中的神经元亚型， 表达NR 1/2C和/或NR 1/2D NMDAR;它们的突触与突触外位置;受体是否 有助于紧张性活跃的谷氨酸电流;美金刚对几个NMDAR反应的影响 皮质中的神经元亚型; NR 2D亚基的遗传缺失如何影响神经元中的NMDAR反应 皮质中的亚型;以及NR 2D亚基基因缺失对美金刚的行为效应的影响。 为了实现这些目标，我们将应用于野生型和突变型啮齿动物，一个强大的组合， 方法，包括脑切片的电生理记录，新的受体识别， 药理学工具和动物行为分析。这项研究将提供基本的 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.