Kim Jinsook, Gale Karen, Kondratyev Alexei
Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
Int J Dev Neurosci. 2010 May;28(3):227-32. doi: 10.1016/j.ijdevneu.2010.02.003. Epub 2010 Feb 17.
Repeated brief seizures, such as those induced by electroconvulsive therapy (ECT), markedly elevate neurotrophic factor levels in the adult rat brain, but it is not known whether a similar response to seizures occurs in immature animals. To address this question, we evoked brief seizures with electroconvulsive shock (ECS) in rat pups at different stages of postnatal development and examined basic fibroblast growth factor (FGF-2), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) proteins in selected brain regions in which these trophic factors are known to increase in the adult rat following ECS-induced seizures. ECS treatments were administered daily (3 episodes/day) over 7 days to rat pups of three different ages: postnatal day (P)1-7, P7-13, or P14-20. Protein levels were measured 6h after the last ECS using Western blotting for FGF-2 in rhinal cortex, ELISA for BDNF and NGF in hippocampus, and NGF in frontal cortex. 7 days of repeated ECS-induced seizures during P1-7 did not alter protein levels for BDNF, FGF-2, or NGF. The repeated seizures during P7-13 affected only BDNF protein, causing a significant elevation of 40% in hippocampus over sham-treated controls. In P14-20 pups, the repeated seizures resulted in a significant increase in BDNF in hippocampus (162% over controls) and FGF-2 in rhinal cortex (34% over controls), while NGF protein did not show a significant change in either hippocampus or frontal cortex. The results suggest that during the first postnatal week there is a resistance to seizure-induced increase in neurotrophic factors, but by the third postnatal week, both BDNF and FGF-2 are elevated substantially in response to repeated seizures. This time-dependent profile suggests that synthesis of these proteins is initially activity-independent, becoming subject to activity-dependent regulation by 3 weeks of age. This maturation of seizure-evoked changes in trophic factors may be important for understanding the impact of ECT and seizures in childhood.
反复短暂发作，如电惊厥治疗（ECT）所诱发的发作，会显著提高成年大鼠大脑中的神经营养因子水平，但尚不清楚未成熟动物是否会对发作产生类似反应。为解决这个问题，我们在出生后不同发育阶段的幼鼠中用电惊厥休克（ECS）诱发短暂发作，并在已知这些营养因子在成年大鼠经ECS诱发发作后会增加的特定脑区检测碱性成纤维细胞生长因子（FGF - 2）、神经生长因子（NGF）和脑源性神经营养因子（BDNF）蛋白。对三个不同年龄的幼鼠进行为期7天的ECS治疗，每天（3次/天）：出生后第（P）1 - 7天、P7 - 13天或P14 - 20天。在最后一次ECS治疗6小时后，使用免疫印迹法检测嗅皮质中的FGF - 2、酶联免疫吸附测定法检测海马体中的BDNF和NGF以及额叶皮质中的NGF来测量蛋白水平。出生后第1 - 7天期间，7天的反复ECS诱发发作并未改变BDNF、FGF - 2或NGF的蛋白水平。出生后第7 - 13天期间的反复发作仅影响BDNF蛋白，导致海马体中BDNF蛋白水平比假手术对照组显著升高40%。在出生后第14 - 20天的幼鼠中，反复发作导致海马体中BDNF显著增加（比对照组高162%），嗅皮质中FGF - 2显著增加（比对照组高34%），而海马体和额叶皮质中的NGF蛋白均未显示出显著变化。结果表明，在出生后的第一周内，幼鼠对发作诱导的神经营养因子增加具有抗性，但到出生后第三周，BDNF和FGF - 2都会因反复发作而大幅升高。这种时间依赖性特征表明，这些蛋白的合成最初与活动无关，到3周龄时开始受到活动依赖性调节。营养因子中发作诱发变化的这种成熟过程对于理解ECT和儿童期发作的影响可能很重要。
