Hashimoto Takanori, Volk David W, Eggan Stephen M, Mirnics Karoly, Pierri Joseph N, Sun Zhuoxin, Sampson Allan R, Lewis David A
Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
J Neurosci. 2003 Jul 16;23(15):6315-26. doi: 10.1523/JNEUROSCI.23-15-06315.2003.
Markers of inhibitory neurotransmission are altered in the prefrontal cortex (PFC) of subjects with schizophrenia, and several lines of evidence suggest that these alterations may be most prominent in the subset of GABA-containing neurons that express the calcium-binding protein, parvalbumin (PV). To test this hypothesis, we evaluated the expression of mRNAs for PV, another calcium-binding protein, calretinin (CR), and glutamic acid decarboxylase (GAD67) in postmortem brain specimens from 15 pairs of subjects with schizophrenia and matched control subjects using single- and dual-label in situ hybridization. Signal intensity for PV mRNA expression in PFC area 9 was significantly decreased in the subjects with schizophrenia, predominantly in layers III and IV. Analysis at the cellular level revealed that this decrease was attributable principally to a reduction in PV mRNA expression per neuron rather than by a decreased density of PV mRNA-positive neurons. In contrast, the same measures of CR mRNA expression were not altered in schizophrenia. These findings were confirmed by findings from cDNA microarray studies using different probes. Across the subjects with schizophrenia, the decrease in neuronal PV mRNA expression was highly associated (r = 0.84) with the decrease in the density of neurons containing detectable levels of GAD67 mRNA. Furthermore, simultaneous detection of PV and GAD67 mRNAs revealed that in subjects with schizophrenia only 55% of PV mRNA-positive neurons had detectable levels of GAD67 mRNA. Given the critical role that PV-containing GABA neurons appear to play in regulating the cognitive functions mediated by the PFC, the selective alterations in gene expression in these neurons may contribute to the cognitive deficits characteristic of schizophrenia.
精神分裂症患者前额叶皮质（PFC）中抑制性神经传递的标志物发生改变，多项证据表明，这些改变在表达钙结合蛋白小白蛋白（PV）的含γ-氨基丁酸（GABA）神经元亚群中可能最为显著。为验证这一假设，我们使用单标记和双标记原位杂交技术，评估了15对精神分裂症患者和匹配的对照受试者的死后脑标本中PV、另一种钙结合蛋白钙视网膜蛋白（CR）和谷氨酸脱羧酶（GAD67）的mRNA表达。精神分裂症患者PFC 9区PV mRNA表达的信号强度显著降低，主要在III层和IV层。细胞水平分析表明，这种降低主要归因于每个神经元PV mRNA表达的减少，而非PV mRNA阳性神经元密度的降低。相比之下，精神分裂症患者CR mRNA表达的相同测量值未发生改变。使用不同探针的cDNA微阵列研究结果证实了这些发现。在精神分裂症患者中，神经元PV mRNA表达的降低与含有可检测水平GAD67 mRNA的神经元密度的降低高度相关（r = 0.84）。此外，PV和GAD67 mRNA的同时检测表明，在精神分裂症患者中，只有55%的PV mRNA阳性神经元具有可检测水平的GAD67 mRNA。鉴于含PV的GABA神经元在调节PFC介导的认知功能中似乎起着关键作用，这些神经元基因表达的选择性改变可能导致精神分裂症的特征性认知缺陷。
