Reductions in the GABAergic neurotransmitter system exist across multiple brain regions in schizophrenia and encompass both pre- and postsynaptic components. While reduced midbrain GABAergic inhibitory neurotransmission may contribute to the hyperdopaminergia thought to underpin psychosis in schizophrenia, molecular changes consistent with this have not been reported. We hypothesised that reduced GABA-related molecular markers would be found in the midbrain of people with schizophrenia and that these would correlate with dopaminergic molecular changes. We hypothesised that downregulation of inhibitory neuron markers would be exacerbated in schizophrenia cases with high levels of neuroinflammation. Eight GABAergic-related transcripts were measured with quantitative PCR, and glutamate decarboxylase (GAD) 65/67 and GABAA alpha 3 (α3) (GABRA3) protein were measured with immunoblotting, in post-mortem midbrain (28/28 and 28/26 control/schizophrenia cases for mRNA and protein, respectively), and analysed by both diagnosis and inflammatory subgroups (as previously defined by higher levels of four pro-inflammatory cytokine transcripts). We found reductions (21 – 44%) in mRNA encoding both presynaptic and postsynaptic proteins, vesicular GABA transporter (VGAT), GAD1, and parvalbumin (PV) mRNAs and four alpha subunits (α1, α2, α3, α5) of the GABAA receptor in people with schizophrenia compared to controls (p < 0.05). Gene expression of somatostatin (SST) was unchanged (p = 0.485). We confirmed the reduction in GAD at the protein level (34%, p < 0.05). When stratifying by inflammation, only GABRA3 mRNA exhibited more pronounced changes in high compared to low inflammatory subgroups in schizophrenia. GABRA3 protein was expressed by 98% of tyrosine hydroxylase-positive neurons and was 23% lower in schizophrenia, though this did not reach statistical significance (p > 0.05). Expression of transcripts for GABAA receptor alpha subunits 2 and 3 (GABRA2, GABRA3) were positively correlated with tyrosine hydroxylase (TH) and dopamine transporter (DAT) transcripts in schizophrenia cases (GABRA2; r > 0.630, GABRA3; r > 0.762, all p < 0.001) but not controls (GABRA2; r < − 0.200, GABRA3; r < 0.310, all p > 0.05). Taken together, our results support a profound disruption to inhibitory neurotransmission in the substantia nigra regardless of inflammatory status, which provides a potential mechanism for disinhibition of nigrostriatal dopamine neurotransmission.

中文翻译：

---

中脑 GABA 能和多巴胺神经元标志物的减少与精神分裂症有关

GABAergic 神经递质系统的减少存在于精神分裂症的多个大脑区域，包括突触前和突触后成分。虽然中脑 GABA 能抑制性神经传递减少可能导致被认为是精神分裂症精神病基础的多巴胺过多症，但与此一致的分子变化尚未见报道。我们假设在精神分裂症患者的中脑中会发现减少的 GABA 相关分子标志物，并且这些标志物与多巴胺能分子变化相关。我们假设在具有高水平神经炎症的精神分裂症病例中，抑制性神经元标志物的下调会加剧。用定量 PCR 测量了八种 GABAergic 相关转录物，和谷氨酸脱羧酶 (GAD) 65/67 和 GABAA α 3 (α3) (GABRA3) 蛋白在死后中脑（mRNA 和蛋白分别为 28/28 和 28/26 对照/精神分裂症病例）中用免疫印迹法测量，并通过诊断和炎症亚组（如先前由较高水平的四种促炎细胞因子转录物定义）进行分析。我们发现编码突触前和突触后蛋白、囊泡 GABA 转运蛋白 (VGAT)、GAD1 和小白蛋白 (PV) mRNA 以及 GABAA 受体的四个 α 亚基 (α1、α2、α3、α5) 的 mRNA 减少 (21 – 44%)精神分裂症患者与对照组相比（p < 0.05）。生长抑素 (SST) 的基因表达没有变化 (p = 0.485)。我们证实了蛋白质水平的 GAD 降低（34%，p < 0.05）。当按炎症分层时，与精神分裂症中的低炎症亚组相比，只有 GABRA3 mRNA 在高炎症亚组中表现出更明显的变化。GABRA3 蛋白在 98% 的酪氨酸羟化酶阳性神经元中表达，在精神分裂症患者中表达率降低 23%，尽管这没有达到统计学意义 (p > 0.05)。GABAA 受体 α 亚基 2 和 3（GABRA2、GABRA3）转录物的表达与精神分裂症病例中的酪氨酸羟化酶（TH）和多巴胺转运蛋白（DAT）转录物呈正相关（GABRA2；r > 0.630，GABRA3；r > 0.762，所有 p < 0.001）但不是对照（GABRA2；r < - 0.200，GABRA3；r < 0.310，所有 p > 0.05）。总之，我们的结果支持对黑质中抑制性神经传递的深刻破坏，无论炎症状态如何，