Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia
Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia
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DOI：
10.1523/jneurosci.4035-04.2005
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发表时间：
2005-01-12
影响因子：
5.3
通讯作者：
Lewis, DA
中科院分区：
文献类型：
--
作者：
Hashimoto, T;Bergen, SE;Lewis, DA
以谷氨酸脱羧酶（GAD(67)）和小白蛋白（PV）的67 kDa异构体等gaba相关基因表达减少为代表的前额叶皮层（PFC）抑制神经元功能障碍似乎与精神分裂症患者的认知缺陷有关。我们研究了脑源性神经营养因子（BDNF）及其受体酪氨酸激酶TrkB介导的信号通路在精神分裂症中gaba相关基因表达改变中的作用。在15对精神分裂症患者和匹配的对照组中，通过原位杂交评估，精神分裂症患者PFC中的BDNF和TrkB mRNA水平均显著降低，而编码神经营养因子-3受体酪氨酸激酶TrkC的mRNA水平不变。在该队列中，TrkB mRNA水平的对内变化与GAD（67）和PV mRNA水平的变化显著相关。在第二组12对受试者中，BDNF、TrkB和GAD(67) mRNA水平也出现了下降。在联合队列中，TrkB和GAD(67) mRNA水平对内变化的相关性明显强于BDNF和GAD(67) mRNA水平变化的相关性。长期暴露于氟哌啶醇后，猴子PFC中的BDNF和TrkB mRNA水平均未发生变化。遗传引入的TrkB表达降低，但BDNF表达不降低，也导致成年小鼠PFC中GAD（67）和PV mRNA水平降低；此外，GAD(67) mRNA表达改变的细胞模式与精神分裂症中的相似。TrkB信号的减少似乎是精神分裂症患者PFC中抑制性神经元功能障碍的基础。
Dysfunction of inhibitory neurons in the prefrontal cortex (PFC), represented by decreased expression of GABA-related genes such as the 67 kDa isoform of glutamate decarboxylase (GAD(67)) and parvalbumin (PV), appears to contribute to cognitive deficits in subjects with schizophrenia. We investigated the involvement of signaling mediated by brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase TrkB in producing the altered GABA-related gene expression in schizophrenia. In 15 pairs of subjects with schizophrenia and matched control subjects, both BDNF and TrkB mRNA levels, as assessed by in situ hybridization, were significantly decreased in the PFC of the subjects with schizophrenia, whereas the levels of mRNA encoding the receptor tyrosine kinase for neurotrophin-3, TrkC, were unchanged. In this cohort, within-pair changes in TrkB mRNA levels were significantly correlated with those in both GAD(67) and PV mRNA levels. Decreased BDNF, TrkB, and GAD(67) mRNA levels were replicated in a second cohort of 12 subject pairs. In the combined cohorts, the correlation between within-pair changes in TrkB and GAD(67) mRNA levels was significantly stronger than the correlation between the changes in BDNF and GAD(67) mRNA levels. Neither BDNF nor TrkB mRNA levels were changed in the PFC of monkeys after a long-term exposure to haloperidol. Genetically introduced decreases in TrkB expression, but not in BDNF expression, also resulted in decreased GAD(67) and PV mRNA levels in the PFC of adult mice; in addition, the cellular pattern of altered GAD(67) mRNA expression paralleled that present in schizophrenia. Decreased TrkB signaling appears to underlie the dysfunction of inhibitory neurons in the PFC of subjects with schizophrenia.