Prenatal NMDA Receptor Antagonism Impaired Proliferation of Neuronal Progenitor, Leading to Fewer Glutamatergic Neurons in the Prefrontal Cortex
Prenatal NMDA Receptor Antagonism Impaired Proliferation of Neuronal Progenitor, Leading to Fewer Glutamatergic Neurons in the Prefrontal Cortex
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DOI：
10.1038/npp.2011.324
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发表时间：
2012-05
影响因子：
7.6
通讯作者：
K. Toriumi;A. Mouri;Shiho Narusawa;Y. Aoyama;Natsumi Ikawa;Lingling Lu;T. Nagai;T. Mamiya;Hyoung‐Chun Kim;T. Nabeshima
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文献类型：
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作者：
K. Toriumi;A. Mouri;Shiho Narusawa;Y. Aoyama;Natsumi Ikawa;Lingling Lu;T. Nagai;T. Mamiya;Hyoung‐Chun Kim;T. Nabeshima
N-甲基-D-天冬氨酸(NMDA)受体是一种谷氨酸受体，在哺乳动物脑发育中起重要作用。我们已经报道，产前使用NMDA受体拮抗剂苯环利定(PCP)会导致长期的行为缺陷和神经化学变化。然而，NMDA受体的产前拮抗作用影响神经发育，导致行为缺陷的机制尚不清楚。在这里，我们报告了产前NMDA受体拮抗剂损害了神经前体细胞的增殖，导致脑室和脑室下区神经前体细胞池的减少。此外，使用专注于神经发生和神经干细胞的PCR阵列，我们评估了导致神经前体细胞增殖受损的基因表达的变化，并发现在出生前接受PCP治疗的小鼠中，Notch2和Ntn1等基因表达异常。因此，前额叶皮质中谷氨酸能神经元的密度降低，可能导致谷氨酸能功能低下。出生前服用五氯苯酚的小鼠直到成年都表现出认知记忆和感觉运动门控的行为缺陷。这些发现提示，在神经发育过程中，NMDA受体可能通过基因表达调控谷氨酸能神经元祖细胞的增殖和成熟。
N-methyl-D-aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long-lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression.