Akbarian S, Kim J J, Potkin S G, Hagman J O, Tafazzoli A, Bunney W E, Jones E G
Department of Anatomy and Neurobiology, University of California-Irvine, USA.
Arch Gen Psychiatry. 1995 Apr;52(4):258-66. doi: 10.1001/archpsyc.1995.03950160008002.
Up-regulation of gamma-aminobutyric acidA (GABAA) 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.
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 microns in diameter, and overall frontal lobe volume. As a control, mRNA levels for type II calcium-calmodulin-dependent protein kinase (CamIIK) were quantified.
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.
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.
精神分裂症患者大脑皮质中γ-氨基丁酸A（GABAA）受体上调及GABA摄取减少，提示GABA能传递改变，这可能是由GABA突触的原发性紊乱或递质产生减少所致。递质产生减少可能是由于GABA生成停止，或是由于细胞死亡或在脑发育过程中未能迁移至皮质而导致GABA神经元丧失。
为区分这些可能性，我们采用原位杂交组织化学、密度测定法和细胞计数法，对精神分裂症患者及匹配对照组背外侧前额叶皮质（DLPFC）中GABA合成关键酶谷氨酸脱羧酶（GAD）67-kd亚型的信使核糖核酸（mRNA）水平、表达GAD mRNA的神经元数量及分层分布进行了量化。将这些数据与神经元总数、直径为8至15微米的小的圆形或椭圆形神经元数量以及额叶总体积进行比较。作为对照，对II型钙/钙调蛋白依赖性蛋白激酶（CamIIK）的mRNA水平进行了量化。
精神分裂症患者I层（40%）和II层（48%）神经元中的GAD mRNA水平显著降低，III至VI层总体降低30%。GAD mRNA水平也有明显的总体降低。CamIIK mRNA水平在样本之间无显著差异。在神经元总数以及小的圆形或椭圆形神经元数量方面未发现差异，而这些神经元应包括大多数GABA细胞。对照组和精神分裂症患者的前额叶灰质和白质体积无显著差异。
精神分裂症患者的前额叶皮质在无明显细胞丢失的情况下GAD表达降低。这可能是由与DLPFC功能减退相关的活性依赖性下调所致。精神分裂症患者DLPFC和额叶体积中细胞数量无明显改变，这也意味着在发育过程中总体皮质神经元迁移未受损害。先前关于精神分裂症患者大脑皮质下白质中神经元分布与对照组相比发生改变的报道，可能表明皮质下板层中迁移或程序性细胞死亡受到干扰，导致精神分裂症患者上层皮质中连接形成改变以及与神经递质相关基因表达的活性依赖性下调。
