Croll S D, Suri C, Compton D L, Simmons M V, Yancopoulos G D, Lindsay R M, Wiegand S J, Rudge J S, Scharfman H E
Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA.
Neuroscience. 1999;93(4):1491-506. doi: 10.1016/s0306-4522(99)00296-1.
Transgenic mice overexpressing brain-derived neurotrophic factor from the beta-actin promoter were tested for behavioral, gross anatomical and physiological abnormalities. Brain-derived neurotrophic factor messenger RNA overexpression was widespread throughout brain. Overexpression declined with age, such that levels of overexpression decreased sharply by nine months. Brain-derived neurotrophic factor transgenic mice had no gross deformities or behavioral abnormalities. However, they showed a significant passive avoidance deficit. This deficit was dependent on continued overexpression, and resolved with age as brain-derived neurotrophic factor transcripts decreased. In addition, the brain-derived neurotrophic factor transgenic mice showed increased seizure severity in response to kainic acid. Hippocampal slices from brain-derived neurotrophic factor transgenic mice showed hyperexcitability in area CA3 and entorhinal cortex, but not in dentate gyrus. Finally, area CA1 long-term potentiation was disrupted, indicating abnormal plasticity. Our data suggest that overexpression of brain-derived neurotrophic factor in the brain can interfere with normal brain function by causing learning impairments and increased excitability. The results also support the hypothesis that excess brain-derived neurotrophic factor could be pro-convulsant in the limbic system.
对从β-肌动蛋白启动子过表达脑源性神经营养因子的转基因小鼠进行了行为、大体解剖学和生理学异常测试。脑源性神经营养因子信使核糖核酸的过表达在整个大脑中广泛存在。过表达随年龄下降，以至于到九个月时过表达水平急剧下降。脑源性神经营养因子转基因小鼠没有明显的畸形或行为异常。然而，它们表现出显著的被动回避缺陷。这种缺陷依赖于持续的过表达，并随着年龄增长而解决，因为脑源性神经营养因子转录本减少。此外，脑源性神经营养因子转基因小鼠对海藻酸的反应显示癫痫发作严重程度增加。脑源性神经营养因子转基因小鼠的海马切片在CA3区和内嗅皮质显示兴奋性过高，但在齿状回没有。最后，CA1区长时程增强被破坏，表明可塑性异常。我们的数据表明，大脑中脑源性神经营养因子的过表达可通过导致学习障碍和兴奋性增加来干扰正常脑功能。结果还支持这样的假说，即过量的脑源性神经营养因子在边缘系统中可能是促惊厥的。
