Laboratory of Molecular Neuroscience, School of Biomedical Science and Medical Research Institute, Tokyo Medical and Dental University, Tokyo Japan.
PLoS One. 2012;7(5):e36853. doi: 10.1371/journal.pone.0036853. Epub 2012 May 11.
Brains of patients with schizophrenia show both neurodevelopmental and functional deficits that suggest aberrant glutamate neurotransmission. Evidence from both genetic and pharmacological studies suggests that glutamatergic dysfunction, particularly with involvement of NMDARs, plays a critical role in the pathophysiology of schizophrenia. However, how prenatal disturbance of NMDARs leads to schizophrenia-associated developmental defects is largely unknown.
METHODOLOGY/PRINCIPAL FINDINGS: Glutamate transporter GLAST/GLT1 double-knockout (DKO) mice carrying the NMDA receptor 1 subunit (NR1)-null mutation were generated. Bouin-fixed and paraffin-embedded embryonic day 16.5 coronal brain sections were stained with hematoxylin, anti-microtubule-associated protein 2 (MAP2), and anti-L1 antibodies to visualize cortical, hippocampal, and olfactory bulb laminar structure, subplate neurons, and axonal projections. NR1 deletion in DKO mice almost completely rescued multiple brain defects including cortical, hippocampal, and olfactory bulb disorganization and defective corticothalamic and thalamocortical axonal projections.
CONCLUSIONS/SIGNIFICANCE: Excess glutamatergic signaling in the prenatal stage compromises early brain development via overstimulation of NMDARs.
精神分裂症患者的大脑表现出神经发育和功能缺陷，表明谷氨酸能神经传递异常。遗传和药理学研究的证据表明，谷氨酸能功能障碍，特别是涉及 NMDA 受体，在精神分裂症的病理生理学中起着关键作用。然而，产前 NMDA 受体功能障碍如何导致与精神分裂症相关的发育缺陷在很大程度上尚不清楚。
方法/主要发现：生成了携带 NMDA 受体 1 亚基（NR1）-null 突变的谷氨酸转运体 GLAST/GLT1 双敲除（DKO）小鼠。用 Bouin 固定和石蜡包埋的胚胎 16.5 天冠状脑切片用苏木精、抗微管相关蛋白 2（MAP2）和抗 L1 抗体染色，以可视化皮质、海马和嗅球层状结构、基板神经元和轴突投射。NR1 在 DKO 小鼠中的缺失几乎完全挽救了多种脑缺陷，包括皮质、海马和嗅球的紊乱以及皮质丘脑和丘脑皮质轴突投射的缺陷。
结论/意义：产前阶段过量的谷氨酸能信号通过 NMDA 受体的过度刺激损害早期大脑发育。
