Cortical Gene Expression After a Conditional Knockout of 67 kDa Glutamic Acid Decarboxylase in Parvalbumin Neurons
Cortical Gene Expression After a Conditional Knockout of 67 kDa Glutamic Acid Decarboxylase in Parvalbumin Neurons
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DOI：
10.1093/schbul/sbw022
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发表时间：
2016-07-01
影响因子：
6.6
通讯作者：
Hashimoto, Takanori
中科院分区：
文献类型：
--
作者：
Georgiev, Danko;Yoshihara, Toru;Hashimoto, Takanori
在患有精神分裂症的受试者的皮层中，谷氨酸脱羧酶67（GAD 67）（主要负责皮层GABA合成的酶）的表达在表达小清蛋白（PV）的GABA神经元的子集中减少。这种GAD 67缺陷伴随着其他GABA相关转录物的皮质水平降低，包括GABA转运蛋白1、PV、脑源性神经营养因子（BDNF）、原肌球蛋白受体激酶B、生长抑素、GABA A受体α 1亚基和KCNS 3钾通道亚基mRNA。相反，另一种GABA合成酶谷氨酸脱羧酶65（GAD 65）的信使RNA（mRNA）水平没有改变。我们通过分析具有PV神经元特异性GAD67敲除的小鼠中这些GABA相关mRNA的皮质水平，来检验这种GABA相关转录水平模式继发于PV神经元中GAD67缺陷的假设。使用原位杂交，我们发现，没有一个检查GABA相关的转录有较低的皮质表达基因敲除小鼠。与此相反，PV，BDNF，KCNS3和GAD 65 mRNA水平在纯合子小鼠中较高。此外，我们的行为测试组合未能检测到感觉运动门控或工作记忆的变化，尽管纯合子小鼠表现出增加的自发活动。这些研究结果表明，减少GAD 67在PV神经元的表达是不是一个上游的GABA相关的转录物，或特征性的行为，在精神分裂症的水平较低的原因。在PV神经元特异性GAD 67敲除小鼠中，PV、BDNF和KCNS 3 mRNA水平的增加可能是继发于GABA合成降低的神经元活性增加的结果，而GAD 65 mRNA的增加可能代表GABA合成增加的代偿反应。
In the cortex of subjects with schizophrenia, expression of glutamic acid decarboxylase 67 (GAD67), the enzyme primarily responsible for cortical GABA synthesis, is reduced in the subset of GABA neurons that express parvalbumin (PV). This GAD67 deficit is accompanied by lower cortical levels of other GABA-associated transcripts, including GABA transporter-1, PV, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B, somatostatin, GABA A receptor a1 subunit, and KCNS3 potassium channel subunit mRNAs. In contrast, messenger RNA (mRNA) levels for glutamic acid decarboxylase 65 (GAD65), another enzyme for GABA synthesis, are not altered. We tested the hypothesis that this pattern of GABA-associated transcript levels is secondary to the GAD67 deficit in PV neurons by analyzing cortical levels of these GABA-associated mRNAs in mice with a PV neuron-specific GAD67 knockout. Using in situ hybridization, we found that none of the examined GABA-associated transcripts had lower cortical expression in the knockout mice. In contrast, PV, BDNF, KCNS3, and GAD65 mRNA levels were higher in the homozygous mice. In addition, our behavioral test battery failed to detect a change in sensorimotor gating or working memory, although the homozygous mice exhibited increased spontaneous activities. These findings suggest that reduced GAD67 expression in PV neurons is not an upstream cause of the lower levels of GABA-associated transcripts, or of the characteristic behaviors, in schizophrenia. In PV neuron- specific GAD67 knockout mice, increased levels of PV, BDNF, and KCNS3 mRNAs might be the consequence of increased neuronal activity secondary to lower GABA synthesis, whereas increased GAD65 mRNA might represent a compensatory response to increase GABA synthesis.