Department of Psychiatry, W1653 Biomedical Science Tower, 200 Lothrop St. University of Pittsburgh, Pittsburgh, PA 15213, USA.
Neurobiol Dis. 2013 Feb;50:179-86. doi: 10.1016/j.nbd.2012.10.018. Epub 2012 Oct 26.
Markers of GABA neurotransmission are altered in multiple regions of the neocortex in individuals with schizophrenia. Lower levels of glutamic acid decarboxylase 67 (GAD67) mRNA and protein, which is responsible for most cortical GABA synthesis, are accompanied by lower levels of GABA membrane transporter 1 (GAT1) mRNA. These alterations are thought to be most prominent in the parvalbumin (PV)-containing subclass of interneurons, which also contain lower levels of PV mRNA. Since GAT1 and PV each reduce the availability of GABA at postsynaptic receptors, lower levels of GAT1 and PV mRNAs have been hypothesized to represent compensatory responses to an upstream reduction in cortical GABA synthesis in schizophrenia. However, such cause-and-effect hypotheses cannot be directly tested in a human illness. Consequently, we used two mouse models with reduced GAD67 expression specifically in PV neurons (PV(GAD67+/-)) or in all interneurons (GABA(GAD67+/-)) and quantified GAD67, GAT1 and PV mRNA levels using methods identical to those employed in studies of schizophrenia. Cortical levels of PV or GAT1 mRNAs were not altered in PV(GAD67+/-) mice during postnatal development or in adulthood. Furthermore, cellular analyses confirmed the predicted reduction in GAD67 mRNA, but failed to show a deficit in PV mRNA in these animals. Levels of PV and GAT1 mRNAs were also unaltered in GABA(GAD67+/-) mice. Thus, mouse lines with cortical reductions in GAD67 mRNA that match or exceed those present in schizophrenia, and that differ in the developmental timing and cell type-specificity of the GAD67 deficit, failed to provide proof-of-concept evidence that lower PV and GAT1 expression in schizophrenia are a consequence of lower GAD67 expression. Together, these findings suggest that the correlated decrements in cortical GAD67, PV and GAT1 mRNAs in schizophrenia may be a common consequence of some other upstream factor.
在精神分裂症患者的新皮层多个区域中，GABA 神经递质的标志物发生改变。谷氨酸脱羧酶 67（GAD67）mRNA 和负责大部分皮质 GABA 合成的蛋白质水平降低，同时 GABA 膜转运体 1（GAT1）mRNA 水平也降低。这些改变被认为在含有 parvalbumin（PV）的中间神经元亚类中最为明显，这些神经元也含有较低水平的 PV mRNA。由于 GAT1 和 PV 都降低了突触后受体 GABA 的可利用性，因此较低水平的 GAT1 和 PV mRNA 被假设为精神分裂症中皮质 GABA 合成减少的上游补偿反应。然而，在人类疾病中，不能直接测试这种因果关系假说。因此，我们使用了两种在 PV 神经元（PV(GAD67+/-)）或所有中间神经元（GABA(GAD67+/-)）中特异性表达减少 GAD67 的小鼠模型，并使用与精神分裂症研究中相同的方法定量了 GAD67、GAT1 和 PV mRNA 水平。在 PV(GAD67+/-) 小鼠的出生后发育或成年期间，PV 或 GAT1 mRNA 的皮质水平没有改变。此外，细胞分析证实了预测的 GAD67 mRNA 减少，但未能在这些动物中显示 PV mRNA 的缺陷。GABA(GAD67+/-) 小鼠中 PV 和 GAT1 mRNA 的水平也没有改变。因此，具有与精神分裂症中存在的 GAD67 mRNA 减少相匹配或超过的皮质 GAD67 mRNA 减少的小鼠系，并且在 GAD67 缺陷的发育时间和细胞类型特异性方面存在差异，未能提供证明较低的 PV 和 GAT1 在精神分裂症中的表达是 GAD67 表达降低的结果的概念验证证据。总之，这些发现表明，在精神分裂症中皮质 GAD67、PV 和 GAT1 mRNA 的相关减少可能是某种其他上游因素的共同后果。
