Akbarian Schahram, Huang Hsien-Sung
Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, 303 Belmont Street, Worcester, 01604, USA.
Brain Res Rev. 2006 Sep;52(2):293-304. doi: 10.1016/j.brainresrev.2006.04.001. Epub 2006 Jun 8.
The 67 and 65 kDa isoforms of glutamic acid decarboxylase, the key enzymes for GABA biosynthesis, are expressed at altered levels in postmortem brain of subjects diagnosed with schizophrenia and related disorders, including autism and bipolar illness. The predominant finding is a decrease in GAD67 mRNA levels, affecting multiple brain regions, including prefrontal and temporal cortex. Postmortem studies, in conjunction with animal models, identified several mechanisms that contribute to the dysregulation of GAD67 in cerebral cortex. These include disordered connectivity formation during development, abnormal expression of Reelin and neural cell adhesion molecule (NCAM) glycoproteins, defects in neurotrophin signaling and alterations in dopaminergic and glutamatergic neurotransmission. These mechanisms are likely to operate in conjunction with genetic risk factors for psychosis, including sequence polymorphisms residing in the promoter of GAD1 (2q31), the gene encoding GAD67. We propose an integrative model, with multiple molecular and cellular mechanisms contributing to transcriptional dysregulation of GAD67 and cortical dysfunction in psychosis.
谷氨酸脱羧酶（GABA生物合成的关键酶）的67 kDa和65 kDa亚型，在被诊断患有精神分裂症及相关疾病（包括自闭症和双相情感障碍）的受试者的死后大脑中表达水平发生改变。主要发现是GAD67 mRNA水平降低，影响多个脑区，包括前额叶和颞叶皮质。死后研究与动物模型相结合，确定了几种导致大脑皮质中GAD67失调的机制。这些机制包括发育过程中连接形成紊乱、Reelin和神经细胞黏附分子（NCAM）糖蛋白的异常表达、神经营养因子信号传导缺陷以及多巴胺能和谷氨酸能神经传递的改变。这些机制可能与精神病的遗传风险因素共同起作用，包括位于GAD1（2q31）启动子中的序列多态性，GAD1是编码GAD67的基因。我们提出了一个综合模型，其中多种分子和细胞机制导致了精神病中GAD67的转录失调和皮质功能障碍。
