Alterations in regional brain metabolism in genetic and pharmacological models of reduced NMDA receptor function
Alterations in regional brain metabolism in genetic and pharmacological models of reduced NMDA receptor function
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DOI：
10.1016/s0006-8993(02)03156-6
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发表时间：
2002-10-04
期刊：
影响因子：
2.9
通讯作者：
Snouwaert, JN
中科院分区：
文献类型：
--
作者：
Duncan, GE;Miyamoto, S;Snouwaert, JN
已经开发了表达低水平NMDA受体的NMDA R1（NR 1）亚基的小鼠品系[Cell 98（1999）427]。这些NR 1亚型小鼠代表了NMDA受体功能降低的实验模型，可能与精神分裂症的病理生理学有关。为了进一步表征发育性NMDA受体功能减退导致的神经生物学表型，通过C-14-2-脱氧葡萄糖（2-DG）摄取的放射自显影分析评估了局部脑代谢活性。此外，通过定量放射自显影术测量配体与NMDA、AMPA和红藻氨酸受体的结合。MK-801与NMDA受体的结合在NR 1低形态小鼠的整个脑中显著降低。然而，在H-3-AMPA或H-3-红藻氨酸盐结合中没有改变在任何检查的区域中是明显的。在NR 1亚形动物中观察到区域2-DG摄取的神经解剖学特异性改变。内侧前额叶和前扣带皮层的相对2-DG摄取减少。改变模式的2-DG摄取也被发现在新皮层区域，与选择性减少摄取层6在额叶区的躯体感觉和运动皮层。这些数据表明，在NR 1亚形动物的皮质回路的改变，并与慢性精神分裂症患者的功能成像研究，通常显示额叶皮质代谢活动减少是一致的。在NR 1缺陷小鼠的尾状核、丘脑、海马和选择的丘脑区域也发现相对2-DG摄取减少。然而，在许多其他脑区没有观察到2-DG摄取的改变。NR 1亚纯型小鼠2-DG摄取的改变与野生型小鼠用选择性NMDA拮抗剂MK-801急性攻击后观察到的改变明显不同。在本工作中发现的NR 1亚纯型小鼠脑2-DG摄取的改变模式，以及先前描述的改变的行为表型，表明小鼠可能提供了一个有价值的模型，以研究新的治疗策略，以抵消慢性发育NMDA受体功能减退的神经生物学后果。(C)2002 Elsevier Science B. V.保留所有权利。
A mouse line has been developed that expresses low levels of the NMDA R1 (NR1) subunit of the NMDA receptor [Cell 98 (1999) 427]. These NR1 hypomorphic mice represent an experimental model of reduced NMDA receptor function that may be relevant to the pathophysiology of schizophrenia. To further characterize the neurobiological phenotype resulting from developmental NMDA receptor hypofunction, regional brain metabolic activity was assessed by autoradiographic analysis of C-14-2-deoxyglucose (2-DG) uptake. In addition, ligand binding to NMDA, AMPA, and kainate receptors was measured by quantitative autoradiography. MK-801 binding to NMDA receptors was reduced markedly throughout the brain of the NR1 hypomorphic mice. However, no alteration in H-3-AMPA or H-3-kainate binding was apparent in any region examined. Neuroanatomically specific alterations in regional 2-DG uptake were observed in the NR1 hypomorphic animals. Reduced relative 2-DG uptake was observed in the medial prefrontal and anterior cingulate cortices. Altered patterns of 2-DG uptake were also found in neocortical regions, with selective reductions of uptake in layer 6 in frontal regions of somatosensory and motor cortices. These data indicate alterations in cortical circuitry in the NR1 hypomorphic animals and are consistent with functional imaging studies in chronic schizophrenia patients which typically show reduced frontal cortical metabolic activity. Reduced relative 2-DG uptake was also found in the caudate, accumbens, hippocampus, and select thalamic regions in the NR1-deficient mice. However, in many other brain regions no alteration in 2-DG uptake was observed. The alterations in 2-DG uptake in the NR1 hypomorphic mice were distinctly different compared to those observed after acute challenge with the selective NMDA antagonist MK-801 in wild-type mice. The altered patterns of brain 2-DG uptake in the NR1 hypomorphic mice found in the present work, together with the altered behavioral phenotypes previously described, suggest that the mice may provide a valuable model to study novel therapeutic strategies to counteract the neurobiological consequences of chronic developmental NMDA receptor hypofunction. (C) 2002 Elsevier Science B.V. All rights reserved.