GENE-EXPRESSION FOR GLUTAMIC-ACID DECARBOXYLASE IS REDUCED WITHOUT LOSS OF NEURONS IN PREFRONTAL CORTEX OF SCHIZOPHRENICS
GENE-EXPRESSION FOR GLUTAMIC-ACID DECARBOXYLASE IS REDUCED WITHOUT LOSS OF NEURONS IN PREFRONTAL CORTEX OF SCHIZOPHRENICS
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DOI：
10.1001/archpsyc.1995.03950160008002
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发表时间：
1995-04-01
影响因子：
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通讯作者：
JONES, EG
中科院分区：
文献类型：
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作者：
AKBARIAN, S;KIM, JJ;JONES, EG
背景资料：精神分裂症患者大脑皮层中γ-氨基丁酸（A）（GABA（A））受体的上调和GABA摄取的减少表明GABA能传递的改变，这可能是由GABA突触的原发性障碍或递质产生的减少引起的。减少的产量可能是由于GABA生产的关闭或GABA神经元的损失所造成的细胞死亡或他们未能迁移到大脑发育过程中的皮质。为了区分这些可能性，我们定量了谷氨酸脱羧酶（GAD）67 kd亚型的信使RNA（mRNA）水平，GAD是GABA合成的关键酶，以及精神分裂症患者和对照组背外侧前额叶皮质（DLPFC）中GAD mRNA表达神经元的数量和层状分布，采用原位杂交组织化学、光密度测定和细胞计数方法。这些数据进行了比较，神经元的总数，小，圆形或卵形神经元的直径8至15 μ m，和整体额叶体积。作为对照，II型钙-钙调蛋白依赖性蛋白激酶（CamIIK）的mRNA水平进行了quantitatives.Results：Schizophrenics显示了显着的下降GAD mRNA水平在神经元的第一层（40%）和第二层（48%）和整体下降30%，在第三至VI层。GAD mRNA水平也有强烈的整体下降。CamIIK mRNA水平在样品之间没有显着差异。在神经元总数和小的、圆形的或卵圆形的神经元中没有发现差异，这些神经元应该包括大多数GABA细胞。前额叶灰质和白色物质的体积没有显着差异对照组和精神分裂症。结论：精神分裂症患者的前额叶皮层GAD的表达减少，在没有显着的细胞损失。这可能是由活动依赖引起的。与DLPFC功能减退相关的下调。精神分裂症患者的DLPFC和额叶体积中细胞数量没有显著变化，这也意味着整个皮质神经元迁移在发育中没有受到影响。以前的报告改变神经元分布在皮层下的精神分裂症的大脑与对照组相比，白色问题可能表明迁移或程序性细胞死亡的皮质基板的干扰，导致改变连接形成在上覆皮层的精神分裂症和活动依赖性下调神经递质相关的基因表达。
Background: Up-regulation of gamma-aminobutyric acid(A) (GABA(A)) receptors and decreased GABA uptake in the cerebral cortex of schizophrenics suggest altered GABAergic transmission, which could be caused by primary disturbance of GABA synapses or by decreased production of the transmitter. Decreased production could be due to a shutdown in GABA production or to loss of GABA neurons caused by cell death or their failure to migrate to the cortex during brain development.Methods: To discriminate between these possibilities, we quantified levels of messenger RNA (mRNA) for the 67-kd isoform of glutamic acid decarboxylase (GAD), the key enzyme in GABA synthesis, and the number and laminar distribution of GAD mRNA-expressing neurons in the dorsolateral prefrontal cortex (DLPFC) of schizophrenics and matched controls, using in situ hybridization-histochemistry, densitometry, and cell-counting methods. These data were compared with the total number of neurons, the number of small, round or ovoid neurons 8 to 15 mu m in diameter, and overall frontal lobe volume. As a control, mRNA levels for type II calcium-calmodulin-dependent protein kinase (CamIIK) were quantified.Results: Schizophrenics showed a pronounced decrease in GAD mRNA levels in neurons of layer I (40%) and layer II (48%) and an overall 30% decrease in layers III to VI. There were also strong overall reductions in GAD mRNA levels. The CamIIK mRNA levels showed no significant differences between samples. No differences were found in the total number of neurons nor in small, round or ovoid neurons, which should include a majority of the GABA cells. Prefrontal gray and white matter volume did not differ significantly between controls and schizophrenics.Conclusions: The prefrontal cortex of schizophrenics shows reduced expression for GAD in the absence of significant cell loss. This may be brought about by an activity-dependent. down-regulation associated with the functional hypoactivity of the DLPFC. The lack of significant alterations in cell numbers in the DLPFC and frontal lobe volume in schizophrenics also implies that overall cortical neuronal migration had not been compromised in development. Previous reports of altered neuronal distribution in the subcortical white matter of schizophrenic brains in comparison with that of controls may indicate disturbances of migration or programmed cell death in the cortical subplate, leading to altered connection formation in the overlying cortex of schizophrenics and activity-dependent down-regulation of neurotransmitter-related gene expression.