Bullock W Michael, Cardon Karen, Bustillo Juan, Roberts Rosalinda C, Perrone-Bizzozero Nora I
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
Am J Psychiatry. 2008 Dec;165(12):1594-603. doi: 10.1176/appi.ajp.2008.07121845. Epub 2008 Oct 15.
Deficits in gamma-aminobutyric acid (GABA) signaling have been described in the prefrontal cortex, limbic system, and cerebellum in individuals with schizophrenia. The purpose of the present study was to further investigate cerebellar gene expression alterations as they relate to decreases in GABAergic transmission by examining the expression of GABAergic markers, N-methyl-d-aspartic-acid (NMDA) receptor subunits, and cerebellum neuromodulators in individuals with schizophrenia.
Subjects were postmortem men with a diagnosis of schizophrenia (N=13) and a postmortem interval-matched non-psychiatric male comparison group (N=13). The authors utilized real-time-quantitative polymerase chain reaction (PCR) to measure mRNA levels of the following GABAergic markers: glutamic acid decarboxylase (GAD) 65 and 67; GABA plasma membrane transporter-1 (GAT-1); GABA type A (GABA(A)) receptor subunits alpha(6), beta(3), and delta; and parvalbumin. In addition, real-time-quantitative PCR was utilized to assess mRNA levels of the NMDA receptor (NR) subunits NR1, NR2-A, NR2-B, NR2-C, and NR2-D as well as the cerebellar neuromodulators glutamate receptor (GluR)-6, kainate-preferring glutamate receptor subunit-2 (KA2), metabotropic glutamate receptor (mGluR)-2 and mGluR3, and neuronal nitric oxide synthase. Measurements for mRNA levels were determined using lateral cerebellar hemisphere tissue from both schizophrenia and comparison subjects.
Schizophrenia subjects showed significant decreases in mRNA levels of GAD(67), GAD(65), GAT-1, mGluR2, and neuronal nitric oxide synthase. Increases in GABA(A)-alpha(6 )and GABA(A)-delta as well as GluR6 and KA2 were also observed. Medication effects on the expression of the same genes were examined in rats treated with either haloperidol (Sprague-Dawley rats [N=16]) or clozapine (Long-Evans rats [N=20]). Both haloperidol and clozapine increased the levels of GAD(67) in the cerebellum and altered the expression of other cerebellar mRNAs.
These findings suggest that GABA transmission is decreased in the cerebellar cortices in individuals with schizophrenia and additional gene expression changes may reflect an attempt to increase GABA neurotransmission at the cerebellar glomerulus.
精神分裂症患者前额叶皮质、边缘系统和小脑中γ-氨基丁酸（GABA）信号传导存在缺陷。本研究的目的是通过检测精神分裂症患者GABA能标志物、N-甲基-D-天冬氨酸（NMDA）受体亚基和小脑神经调质的表达，进一步研究与GABA能传递减少相关的小脑基因表达变化。
研究对象为确诊为精神分裂症的男性尸检者（N = 13）和尸检间隔匹配的非精神疾病男性对照组（N = 13）。作者利用实时定量聚合酶链反应（PCR）检测以下GABA能标志物的mRNA水平：谷氨酸脱羧酶（GAD）65和67；GABA质膜转运体-1（GAT-1）；A型GABA（GABA(A)）受体亚基α(6)、β(3)和δ；以及小白蛋白。此外，利用实时定量PCR评估NMDA受体（NR）亚基NR1、NR2-A、NR2-B、NR2-C和NR2-D以及小脑神经调质谷氨酸受体（GluR）-6、红藻氨酸优先型谷氨酸受体亚基-2（KA2）、代谢型谷氨酸受体（mGluR）-2和mGluR3以及神经元型一氧化氮合酶的mRNA水平。使用精神分裂症患者和对照组受试者的小脑外侧半球组织测定mRNA水平。
精神分裂症患者的GAD(67)、GAD(65)、GAT-1、mGluR2和神经元型一氧化氮合酶的mRNA水平显著降低。还观察到GABA(A)-α(6)和GABA(A)-δ以及GluR6和KA2增加。在用氟哌啶醇（斯普拉格-道利大鼠 [N = 16]）或氯氮平（长-伊文斯大鼠 [N = 20]）治疗的大鼠中检查了药物对相同基因表达的影响。氟哌啶醇和氯氮平均增加了小脑中GAD(67)的水平，并改变了其他小脑mRNA的表达。
这些发现表明，精神分裂症患者小脑皮质中的GABA传递减少，其他基因表达变化可能反映了在小脑小球处增加GABA神经传递的尝试。
