Department of Psychiatry, University of Pittsburgh, Pittsburgh, USA.
Am J Psychiatry. 2012 Oct;169(10):1082-91. doi: 10.1176/appi.ajp.2012.12030305.
In schizophrenia, alterations within the prefrontal cortical GABA system appear to be most prominent in neurons that contain parvalbumin or somatostatin but not calretinin. The transcription factors Lhx6 and Sox6 play critical roles in the specification, migration, and maturation of parvalbumin and somatostatin neurons, but not calretinin neurons, and continue to be strongly expressed in this cell type-specific manner in the prefrontal cortex of adult humans. The authors investigated whether Lhx6 and/or Sox6 mRNA levels are deficient in schizophrenia, which may contribute to cell type-specific disturbances in cortical parvalbumin and somatostatin neurons.
The authors used quantitative PCR and in situ hybridization with film and grain counting analyses to quantify mRNA levels in postmortem samples of prefrontal cortex area 9 of 42 schizophrenia subjects and 42 comparison subjects who had no psychiatric diagnoses in life, as well as antipsychotic-exposed monkeys.
In schizophrenia subjects, the authors observed lower mRNA levels for Lhx6, parvalbumin, somatostatin, and glutamate decarboxylase (GAD67; the principal enzyme in GABA synthesis), but not Sox6 or calretinin. Cluster analysis revealed that a subset of schizophrenia subjects consistently showed the most severe deficits in the affected transcripts. Grain counting analyses revealed that some neurons that normally express Lhx6 were not detectable in schizophrenia subjects. Finally, lower Lhx6 mRNA levels were not attributable to psychotropic medications or illness chronicity.
These data suggest that in a subset of individuals with schizophrenia, Lhx6 deficits may contribute to a failure of some cortical parvalbumin and somatostatin neurons to successfully migrate or develop a detectable GABA-ergic phenotype.
在精神分裂症中，前额皮质 GABA 系统的改变似乎在含有 parvalbumin 或 somatostatin 但不含 calretinin 的神经元中最为明显。转录因子 Lhx6 和 Sox6 在 parvalbumin 和 somatostatin 神经元的特化、迁移和成熟中发挥关键作用，但不影响 calretinin 神经元，并且在成年人类前额皮质中以这种细胞类型特异性的方式继续强烈表达。作者研究了 Lhx6 和/或 Sox6 mRNA 水平是否在精神分裂症中缺乏，这可能导致皮质 parvalbumin 和 somatostatin 神经元的细胞类型特异性紊乱。
作者使用定量 PCR 和膜和颗粒计数分析的原位杂交技术，对 42 名精神分裂症患者和 42 名无精神病史的对照患者以及接受抗精神病药物治疗的猴子的前额皮质 9 区死后样本进行了 mRNA 水平的定量。
在精神分裂症患者中，作者观察到 Lhx6、parvalbumin、somatostatin 和谷氨酸脱羧酶（GAD67；GABA 合成的主要酶）的 mRNA 水平降低，但 Sox6 或 calretinin 水平没有降低。聚类分析显示，一部分精神分裂症患者的受影响转录本始终表现出最严重的缺陷。颗粒计数分析显示，一些正常表达 Lhx6 的神经元在精神分裂症患者中无法检测到。最后，Lhx6 mRNA 水平降低与精神药物或疾病慢性期无关。
这些数据表明，在一部分精神分裂症患者中，Lhx6 缺陷可能导致一些皮质 parvalbumin 和 somatostatin 神经元未能成功迁移或发育出可检测的 GABA 能表型。
