Unit for Multimodal Imaging Genetics, Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, NIH, Bethesda, Maryland 20892, USA.
J Neurosci. 2011 Aug 10;31(32):11628-32. doi: 10.1523/JNEUROSCI.1529-11.2011.
NRG1-ErbB4 signaling controls inhibitory circuit development in the mammalian cortex through ErbB4-dependent regulation of GABAergic interneuron connectivity. Common genetic variation in ErbB4 (rs7598440) has been associated with ErbB4 messenger RNA levels in the human cortex and risk for schizophrenia. Recent work demonstrates that Erbb4 is expressed exclusively on inhibitory interneurons, where its presence on parvalbumin-positive cells mediates the effects of NRG1 on inhibitory circuit formation in the cortex. We therefore hypothesized that genetic variation in ErbB4 at rs7598440 would impact indices of GABA concentration in the human cortex. We tested this hypothesis in 116 healthy volunteers by measuring GABA and GLX (glutamate + glutamine) with proton magnetic resonance spectroscopy in the dorsal anterior cingulate gyrus. ErbB4 rs7598440 genotype significantly predicted cortical GABA concentration (p = 0.014), but not GLX (p = 0.51), with A allele carriers having higher GABA as predicted by the allelic impact on ErbB4 expression. These data establish an association of ErbB4 and GABA in human brain and have implications for understanding the pathogenesis of schizophrenia and other psychiatric disorders.
NRG1-ErbB4 信号通过 ErbB4 依赖性调节 GABA 能中间神经元连接控制哺乳动物皮层中的抑制性回路发育。ErbB4（rs7598440）中的常见遗传变异与人类皮层中的 ErbB4 信使 RNA 水平和精神分裂症风险相关。最近的研究表明，Erbb4 仅在抑制性中间神经元上表达，其在 Parvalbumin 阳性细胞上的存在介导了 NRG1 对皮层抑制性回路形成的影响。因此，我们假设 ErbB4 中的 rs7598440 遗传变异会影响人类皮层中的 GABA 浓度指数。我们通过在背侧前扣带皮层测量质子磁共振波谱中的 GABA 和 GLX（谷氨酸+谷氨酰胺），在 116 名健康志愿者中测试了这一假设。ErbB4 rs7598440 基因型显著预测了皮层 GABA 浓度（p = 0.014），但不预测 GLX（p = 0.51），A 等位基因携带者的 GABA 浓度高于 ErbB4 表达的等位基因影响所预测的水平。这些数据在人类大脑中确立了 ErbB4 和 GABA 之间的关联，并对理解精神分裂症和其他精神疾病的发病机制具有重要意义。
