Subchronic MK-801 treatment during adolescence induces long-term, not permanent, excitatory-inhibitory imbalance in the rat hippocampus
Subchronic MK-801 treatment during adolescence induces long-term, not permanent, excitatory-inhibitory imbalance in the rat hippocampus
复制标题
青春期亚慢性 MK-801 治疗会导致大鼠海马体出现长期而非永久性的兴奋抑制失衡
DOI：
10.1016/j.ejphar.2019.172807
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发表时间：
2020-01-15
影响因子：
5
通讯作者：
Si, Tian-Mei
中科院分区：
文献类型：
--
作者：
Ma, Yu-Nu;Sun, Ya-Xin;Si, Tian-Mei
青春期是兴奋性和抑制性（E/I）神经传递的关键神经发育时期，并且经常见证精神分裂症的典型发作。一种可能性是，青少年神经发育过程的破坏可能会产生类似精神分裂症的行为和神经生物学异常。我们之前报道过，用 N-甲基-D-天冬氨酸 (NMDA) 受体拮抗剂 MK-801 对青春期动物进行亚慢性治疗会导致大鼠内侧前额叶皮层的认知缺陷和中间神经元密度降低，并且这些变化在 MK-801 暴露后持续一周。然而，目前尚不清楚这种治疗如何影响海马体的 E/I 平衡，长期以来，海马体与精神分裂症的病理生理学有关。在这里，我们检查了接受 MK-801（0.2 mg/kg，腹腔注射，14 天）治疗的青春期大鼠的海马 E/I 生物标志物，发现在 MK-801 暴露后 24 小时和 7 天，囊泡谷氨酸转运蛋白 1 (VGluT1) 和囊泡 γ-氨基丁酸 (GABA) 转运蛋白 (VGAT) 的表达水平比率有所增加。有趣的是，两个时间点 VGluT1/VGAT 比率的增加分别是由 VGluT1 表达上调和 VGAT 表达下调驱动的。暴露于 MK-801 后 14 天，VGAT 表达持续下降，两周后恢复。没有观察到海马中间神经元密度的变化。在行为上，暴露 MK-801 后，治疗在 24 小时而非 14 天降低了前脉冲抑制。综上所述，这些结果表明，青春期亚慢性 NMDA 受体阻断会引起大鼠海马长期但非永久性的 E/I 失衡，这可能归因于短期谷氨酸能传递失调和长期 GABA 能传递失调。
Adolescence is a critical neurodevelopmental period for both excitatory and inhibitory (E/I) neurotransmission and often witnesses the typical onsets of schizophrenia. One possibility is that disruptions in adolescent neurodevelopmental processes may produce schizophrenia-like behavioral and neurobiological abnormalities. We previously reported that subchronic treatment of adolescent animals with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 induced cognitive deficits and reduced interneuron densities in rat medial prefrontal cortex, and these changes persisted one week after MK-801 exposure. However, it remains unclear how this treatment may affect E/I balance in hippocampus, which has long been associated with the pathophysiology of schizophrenia. Here, we examined hippocampal E/I biomarkers in adolescent rats treated with MK-801 (0.2 mg/ kg, i.p., 14 days) and found increases in the ratio of the expression levels of vesicular glutamate transporter-1 (VGluT1) and vesicular gamma-aminobutyric acid (GABA) transporter (VGAT) 24 h and 7 days after MK-801 exposure. Interestingly, the increased VGluT1/VGAT ratio at the two time points was driven by upregulated VGluT1 expression and downregulated VGAT expression, respectively. The decrease in VGAT expression persisted 14 days after MK-801 exposure and recovered two weeks later. No alterations in hippocampal interneuron densities were observed. Behaviorally, the treatment decreased prepulse inhibition at 24 h but not 14 days, after MK-801 exposure. Taken together, these results demonstrate that subchronic NMDA receptor blockade during adolescence induces long-term, but not permanent, E/I imbalance in the rat hippocampus, which could be attributed to the dysregulation of glutamatergic transmission in the short term and of GABAergic transmission in the long term.