Abstract：
Dysregulation of striatal dopamine is considered to be an important driver of pathophysiological processes in schizophrenia. Despite being one of the main origins of dopaminergic input to the striatum, the (dys)functioning of the substantia nigra (SN) has been relatively understudied in schizophrenia. Hence, this paper aims to review different molecular aspects of nigral functioning in patients with schizophrenia compared to healthy controls by integrating post-mortem and molecular imaging studies. We found evidence for hyperdopaminergic functioning in the SN of patients with schizophrenia (i.e. increased AADC activity in antipsychotic-free/-naïve patients and elevated neuromelanin accumulation). Reduced GABAergic inhibition (i.e. decreased density of GABAergic synapses, lower VGAT mRNA levels and lower mRNA levels for GABAA receptor subunits), excessive glutamatergic excitation (i.e. increased NR1 and Glur5 mRNA levels and a reduced number of astrocytes), and several other disturbances implicating the SN (i.e. immune functioning and copper concentrations) could potentially underlie this nigral hyperactivity and associated striatal hyperdopaminergic functioning in schizophrenia. These results highlight the importance of the SN in schizophrenia pathology and suggest that some aspects of molecular functioning in the SN could potentially be used as treatment targets or biomarkers.
摘要：
纹状体多巴胺的失调被认为是精神分裂症病理生理过程的重要驱动因素。尽管是纹状体多巴胺能输入的主要来源之一，在精神分裂症中，对黑质（SN）的（dys）功能的研究相对不足。因此，本文旨在通过整合验尸和分子影像学研究，综述精神分裂症患者与健康对照者的不同分子功能。我们在精神分裂症患者的SN中发现了高多巴胺能功能的证据（即无抗精神病药/初治患者的AADC活性增加和神经黑色素积累升高）。减少GABA能抑制（即GABA能突触的密度降低，较低的VGATmRNA水平和较低的GABAA受体亚基mRNA水平)，过度的谷氨酸能兴奋（即NR1和Glur5mRNA水平增加和星形胶质细胞数量减少），以及涉及SN的其他几种障碍（即免疫功能和铜浓度）可能是精神分裂症中这种黑质过度活动和相关的纹状体高多巴胺能功能的潜在基础。这些结果强调了SN在精神分裂症病理学中的重要性，并表明SN中分子功能的某些方面可能被用作治疗靶标或生物标志物。
