Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts, 02118, USA.
Exp Neurol. 2010 Nov;226(1):207-17. doi: 10.1016/j.expneurol.2010.09.001. Epub 2010 Sep 9.
Parkinson's disease (PD) patients typically suffer from motor disorders but mild to severe cognitive deficits can also be present. Neuropathology of PD primarily involves loss of dopaminergic neurons in the substantia nigra, pars compacta, although more widespread pathology from the brainstem to the cerebral cortex occurs at different stages of the disease. Cognitive deficits in PD are thought to involve the cerebral cortex, and imaging studies have identified the dorsolateral prefrontal cortex (DLPFC) as a possible site for some of the symptoms. GABAergic neurons in the cerebral cortex play a key role in the modulation of pyramidal neurons and alterations in muscimol binding to GABA(A) receptors have been reported in Brodmann area 9 (BA9) of the prefrontal cortex in PD patients (Nishino et al., 1988). In order to further assess the likelihood that GABAergic activity is altered in the prefrontal cortex in PD, gene expression of the 67 kilodalton isoform of the GABA-synthesizing enzyme, glutamic acid decarboxylase (GAD67 encoded by the GAD1 gene), was examined in BA9 of post-mortem brains from 19 patients and 20 controls using isotopic in situ hybridization histochemistry. GAD67 mRNA labeling was examined and quantified on X-ray films and emulsion radioautographs. We show that GAD67 mRNA labeling is significantly lower in PD compared to control cases. Analysis of emulsion radioautographs indicates that GAD67 mRNA labeling is decreased in individual neurons and is not paralleled by a decrease in the number of GAD67 mRNA-labeled neurons. Analysis of expression data from a microarray study performed in 29 control and 33 PD samples from BA9 confirms that GAD67 expression is decreased in PD. Another finding from the microarray study is a negative relationship between GAD67 mRNA expression and age at death. Altogether, the results support the possibility that GABAergic neurotransmission is impaired in the DLPFC in PD, an effect that may be involved in some of the behavioral deficits associated with the disease.
帕金森病（PD）患者通常患有运动障碍，但也可能存在轻度至重度认知缺陷。PD 的神经病理学主要涉及黑质致密部的多巴胺能神经元丧失，尽管在疾病的不同阶段，从脑干到大脑皮层的更广泛的病理学也会发生。PD 中的认知缺陷被认为涉及大脑皮层，影像学研究已经确定背外侧前额叶皮层（DLPFC）是一些症状的可能部位。大脑皮层中的 GABA 能神经元在调节锥体神经元中起着关键作用，并且已经报道 PD 患者的前额叶皮层 Brodmann 区 9（BA9）中 muscimol 与 GABA(A) 受体的结合发生改变（Nishino 等人，1988 年）。为了进一步评估 PD 中前额叶皮层 GABA 能活性改变的可能性，使用同位素原位杂交组织化学技术，在 19 名患者和 20 名对照者的死后大脑 BA9 中，检查了 GABA 合成酶 67 千道尔顿同工型的基因表达，即谷氨酸脱羧酶（GAD1 基因编码的 GAD67）。使用 X 射线胶片和乳胶放射自显影对 GAD67 mRNA 标记进行了检查和量化。我们发现，与对照病例相比，PD 中的 GAD67 mRNA 标记显著降低。乳胶放射自显影分析表明，GAD67 mRNA 标记在单个神经元中减少，并且与 GAD67 mRNA 标记神经元的数量减少不成比例。对来自 29 个对照和 33 个 PD 样本的 BA9 进行的微阵列研究的表达数据进行分析，证实了 PD 中 GAD67 表达降低。微阵列研究的另一个发现是 GAD67 mRNA 表达与死亡时年龄之间的负相关关系。总的来说，这些结果支持了 GABA 能神经传递在 PD 的 DLPFC 中受损的可能性，这种效应可能与疾病相关的一些行为缺陷有关。
