Serine racemase deletion disrupts memory for order and alters cortical dendritic morphology.
Serine racemase deletion disrupts memory for order and alters cortical dendritic morphology.
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DOI：
10.1111/j.1601-183x.2010.00656.x
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发表时间：
2011-03
期刊：
影响因子：
--
通讯作者：
Eichenbaum H
中科院分区：
文献类型：
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作者：
DeVito LM;Balu DT;Kanter BR;Lykken C;Basu AC;Coyle JT;Eichenbaum H
有大量证据表明 N-甲基-d-天冬氨酸受体 (NMDAR) 与记忆和认知有关。也有人认为，NMDAR 功能减退可能是精神分裂症患者认知缺陷的基础，因为在精神分裂症患者死后大脑中发现了形态学变化，包括前额皮质 (PFC) 锥体神经元树突结构的改变。在这里，我们使用 NMDAR 功能减退的遗传模型，即丝氨酸消旋酶敲除（SR−/−）小鼠，其中小鼠丝氨酸消旋酶基因的第一个编码外显子已被删除，以探索 d-丝氨酸在调节认知功能以及树突结构中的作用。物体识别和气味序列测试显示，SR -/− 小鼠在不同的经历中表现出对事件顺序的显着破坏；然而，SR−/−动物在检测新物体和空间位移方面没有受到损害，并且在传递推理测试中表现出完整的关系记忆。此外，SR−/−小鼠表现出正常的社交能力和对社交新奇事物的偏好。 SR−/− 小鼠内侧 PFC 中的神经元表现出顶树突的复杂性、总长度和棘密度的减少。这些发现表明，d-丝氨酸对于认知的特定方面以及调节 mPFC 中锥体神经元的树突形态很重要。此外，他们认为 NMDAR 功能减退可能在一定程度上导致与精神分裂症相关的认知缺陷和突触变化，并强调该信号通路作为治疗干预的潜在目标。
There is substantial evidence implicating N-methyl-d-aspartate receptors (NMDARs) in memory and cognition. It has also been suggested that NMDAR hypofunction might underlie the cognitive deficits observed in schizophrenia since morphological changes, including alterations in the dendritic architecture of pyramidal neurons in the prefrontal cortex (PFC), have been reported in the schizophrenic brain post mortem. Here, we used a genetic model of NMDAR hypofunction, a serine racemase knockout (SR−/−) mouse in which the first coding exon of the mouse serine racemase gene has been deleted, to explore the role of d-serine in regulating cognitive functions as well as dendritic architecture. SR −/− mice exhibited a significantly disrupted representation of the order of events in distinct experiences as revealed by object recognition and odor sequence tests; however, SR −/− animals were unimpaired in the detection of novel objects and in spatial displacement, and showed intact relational memory in a test of transitive inference. In addition, SR −/− mice exhibited normal sociability and preference for social novelty. Neurons in the medial PFC of SR−/− mice displayed reductions in the complexity, total length, and spine density of apical dendrites. These findings demonstrate that d-serine is important for specific aspects of cognition, as well as in regulating dendritic morphology of pyramidal neurons in the mPFC. Moreover, they suggest that NMDAR hypofunction might, in part, be responsible for the cognitive deficits and synaptic changes associated with schizophrenia, and highlight this signaling pathway as a potential target for therapeutic intervention.