Schizophrenia-like GABAergic gene expression deficits in cerebellar Golgi cells from rats chronically exposed to low-dose phencyclidine
Schizophrenia-like GABAergic gene expression deficits in cerebellar Golgi cells from rats chronically exposed to low-dose phencyclidine
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DOI：
10.1016/j.neuint.2009.07.010
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发表时间：
2009-12-01
影响因子：
4.2
通讯作者：
Perrone-Bizzozero, Nora I.
中科院分区：
文献类型：
--
作者：
Bullock, W. Michael;Bolognani, Federico;Perrone-Bizzozero, Nora I.
精神分裂症最一致的发现之一是在特定的中间神经元群体中，γ-氨基丁酸（GABA）合成酶谷氨酸脱羧酶（67）[GAD(67)]和谷氨酸脱羧酶（65）[GAD(65)]的表达降低。这种功能障碍在包括前额叶皮质、海马体和小脑在内的多个脑区都能观察到。为了理解这种GABA缺乏的机制，我们研究了N -甲基 - D -天冬氨酸受体（NMDAR）拮抗剂苯环己哌啶（PCP）的作用，它在人类和动物模型中都会引发类似精神分裂症的症状，采用的是慢性、低剂量暴露模式。成年大鼠以2.58毫克/千克/天的剂量腹腔注射PCP，持续一个月，之后通过定量逆转录聚合酶链反应（qRT - PCR）检测小脑中各种γ-氨基丁酸能细胞的信使核糖核酸（mRNA）和其他神经调节剂的水平。给予PCP降低了GAD(67)、GAD(65)以及突触前GABA转运体GAT - 1的表达，并增加了γ-氨基丁酸A（GABA(A)）受体亚单位，这与在精神分裂症患者中观察到的情况相似。此外，我们发现两种高尔基体细胞选择性NMDAR亚单位，即NR2B和NR2D的mRNA水平在PCP处理的大鼠中降低了。而且，我们发现GAD(67)表达的缺陷仅局限于这些中间神经元。脑片电生理研究表明，急性暴露于低剂量PCP会降低高尔基体细胞的自发放电，这表明这些神经元对N -甲基 - D -天冬氨酸受体拮抗作用特别敏感。总之，我们的研究结果表明，大鼠慢性暴露于低水平的PCP可模拟精神分裂症患者小脑中所报道的γ-氨基丁酸能改变（布洛克等人，2008年。《美国精神病学杂志》165卷，1594 - 1603页），进一步支持了这种动物模型的有效性。（C）2009爱思唯尔有限公司。保留所有权利。
One of the most consistent findings in schizophrenia is the decreased expression of the GABA synthesizing enzymes GAD(67) and GAD(65) in specific interneuron populations. This dysfunction is observed in distributed brain regions including the prefrontal cortex, hippocampus, and cerebellum. In an effort to understand the mechanisms for this GABA deficit, we investigated the effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist phencyclidine (PCP), which elicits schizophrenia-like symptoms in both humans and animal models, in a chronic, low-dose exposure paradigm. Adult rats were given PCP at a dose of 2.58 mg/kg/day i.p. for a month, after which levels of various GABAergic cell mRNAs and other neuromodulators were examined in the cerebellum by qRT-PCR. Administration of PCP decreased the expression of GAD(67), GAD(65), and the presynaptic GABA transporter GAT-1, and increased GABA(A) receptor subunits similar to those seen in patients with schizophrenia. Additionally, we found that the mRNA levels of two Golgi cell selective NMDAR subunits, NR2B and NR2D, were decreased in PCP-treated rats. Furthermore, we localized the deficits in GAD(67) expression solely to these interneurons. Slice electrophysiological studies showed that spontaneous firing of Golgi cells was reduced by acute exposure to low-dose PCP, suggesting that these neurons are particularly vulnerable to NMDA receptor antagonism. In conclusion, our results demonstrate that chronic exposure to low levels of PCP in rats mimics the GABAergic alterations reported in the cerebellum of patients with schizophrenia (Bullock et al., 2008. Am. J. Psychiatry 165, 1594-1603), further supporting the validity of this animal model. (C) 2009 Elsevier Ltd. All rights reserved.