Schizophrenia Research Institute, Sydney, Australia.
Am J Psychiatry. 2010 Dec;167(12):1479-88. doi: 10.1176/appi.ajp.2010.09060784. Epub 2010 Nov 1.
The onset of schizophrenia symptoms in late adolescence implies a neurodevelopmental trajectory for the disease. Indeed, the γ-aminobutyric acid (GABA) inhibitory system shows protracted development, and GABA-ergic deficits are widely replicated in postmortem schizophrenia studies. The authors examined expression of several interneuron markers across postnatal human development and in schizophrenia to assess whether protracted development of certain interneuron subpopulations may be associated with a particular vulnerability in schizophrenia.
RNA was extracted postmortem from dorsolateral prefrontal cortex of individuals from age 6 weeks to 49 years (N=68) and from a cohort of normal comparison subjects and schizophrenia patients (N=74, 37 pairs). Expression levels of parvalbumin, cholecystokinin, somatostatin, neuropeptide Y, calretinin, calbindin, and vasoactive intestinal peptide were measured by quantitative reverse transcription-polymerase chain reaction. Changes in calretinin protein levels were examined by Western blot.
Interneuron marker genes followed one of three general expression profiles: either increasing (parvalbumin, cholecystokinin) or decreasing (somatostatin, calretinin, neuropeptide Y) in expression over postnatal life, with the most dramatic changes seen in the first few years before reaching a plateau; or increasing to peak expression in the toddler years before decreasing (calbindin, vasoactive intestinal peptide). mRNA expression of all genes, with the exception of calbindin (which increased), showed a reduction (8%-31%) in schizophrenia. Somatostatin showed the most dramatic reduction (31%) in schizophrenia.
It appears that a heterogeneous population of interneurons is implicated in schizophrenia. Further studies are needed to determine whether specific interneuron subpopulations are altered or whether common or distinct upstream pathways are responsible for interneuron deficits in schizophrenia.
精神分裂症症状在青春期后期出现意味着该疾病存在神经发育轨迹。实际上，γ-氨基丁酸（GABA）抑制系统的发育过程较为持久，并且 GABA 能缺陷在精神分裂症的死后研究中得到了广泛的复制。作者在人类出生后发育的各个阶段以及精神分裂症中检查了几种中间神经元标志物的表达，以评估特定中间神经元亚群的发育是否与精神分裂症的特定易感性有关。
作者从年龄为 6 周至 49 岁的个体（N=68）和正常对照组和精神分裂症患者（N=74，37 对）的背外侧前额叶皮层中提取死后的 RNA。通过定量逆转录聚合酶链反应测量了 parvalbumin、胆囊收缩素、生长抑素、神经肽 Y、钙调蛋白、钙结合蛋白和血管活性肠肽的表达水平。通过 Western blot 检查 calretinin 蛋白水平的变化。
中间神经元标记基因遵循三种一般表达谱之一：在出生后生命中表达增加（parvalbumin、胆囊收缩素）或减少（生长抑素、钙调蛋白、神经肽 Y），在最初几年中变化最大，然后达到一个平台；或者在幼儿期达到峰值表达后减少（钙结合蛋白、血管活性肠肽）。除了 calbindin（增加）之外，所有基因的 mRNA 表达都减少（8％-31％）在精神分裂症中。生长抑素在精神分裂症中减少最为显著（31％）。
似乎有一个异质的中间神经元群体与精神分裂症有关。需要进一步的研究来确定特定的中间神经元亚群是否改变，或者共同或不同的上游途径是否负责精神分裂症中的中间神经元缺陷。
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