Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
Neurobiol Dis. 2012 Feb;45(2):692-700. doi: 10.1016/j.nbd.2011.10.013. Epub 2011 Oct 25.
Clinical studies have suggested that children experiencing a febrile seizure (FS) before the age of 1year have persistent deficits, but it is unknown whether these seizures lead to permanent cortical reorganization and alterations in function. A FS on the background of increased genetic seizure susceptibility may also lead to negative long-term consequences. Alterations in neocortical motor map expression provide a measure of neocortical reorganization and have been reported in both adults with frontal lobe epilepsy and following seizure induction in experimental models. The objectives of the present study were to determine whether (1) an infantile FS leads to changes to motor map expression in adulthood; (2) long-term cortical reorganization is a function of the age at FS or genetic seizure susceptibility; and (3) different levels of GABA(A) or glutamate receptor subunits or cation-chloride-co-transporters (CCCs) at the time of FS correlate with alterations to motor map expression.
FSs were induced in postnatal day 10 (P10) or P14 Long-Evans (LE) rats or in P14 seizure-prone FAST rats by the administration of the bacterial endotoxin lipopolysaccharide (LPS) and a subconvulsant dose of kainic acid. Ten weeks later intracortical microstimulation was performed to generate motor maps of forelimb movement representations. Sensorimotor neocortex samples were also dissected from naïve P10 FAST and P10 and P14 LE pups for western blotting with antibodies against various GABA(A), NMDA, and AMPA receptor subunits and for CCCs.
Adult FAST rats had larger motor maps with lower stimulation thresholds after a FS at P14, while adult LE rats had significantly lower map stimulation thresholds but similar sized maps after a FS at P10 compared to controls. There were no differences in neocortical motor map size or stimulation thresholds in adult LE rats after a FS at P14. Both P10 LE and P14 FAST rats had significantly lower levels of the GABA(A) receptor α1 subunit, higher levels of the α2 subunit, and a higher NKCC1/KCC2 ratio in the sensorimotor cortex compared with the P14 LE rat. In addition, the P14 FAST rats had lower levels of the GluR2 and NR2A receptor subunits in the sensorimotor cortex compared with the P14 LE rats.
A single infantile FS can have long-term effects on neocortical reorganization in younger individuals and those with underlying seizure susceptibility. These changes may be related to an increased level of excitability in the neocortex of younger or genetically seizure-prone rats, as suggested by immaturity of their GABAergic and CCC systems. Given the high incidence of FSs in children, it will be important to gain a better understanding of how age and genetic seizure predisposition may contribute to the long-term sequelae of these events.
临床研究表明，1 岁以下经历热性惊厥（FS）的儿童存在持续性缺陷，但尚不清楚这些惊厥是否导致皮质永久性重组和功能改变。在遗传易感性增加的背景下发生 FS 也可能导致负面的长期后果。新皮层运动图表达的改变提供了新皮层重组的衡量标准，在额叶癫痫患者和实验模型中的癫痫诱导后均有报道。本研究的目的是确定：（1）婴儿 FS 是否会导致成年后运动图表达的改变；（2）长期皮质重组是 FS 年龄或遗传易感性的功能；（3）FS 时 GABA(A)或谷氨酸受体亚基或阳离子-氯离子共转运体（CCC）的不同水平是否与运动图表达的改变相关。
通过给予细菌内毒素脂多糖（LPS）和亚惊厥剂量的海人酸，在出生后第 10 天（P10）或 P14 长耳（LE）大鼠或 P14 易发性 FAST 大鼠中诱导 FS。10 周后，进行皮层内微刺激以产生前肢运动代表的运动图。还从天真的 P10 FAST 和 P10 和 P14 LE 幼仔中分离出感觉运动新皮层样本，用于针对各种 GABA(A)、NMDA 和 AMPA 受体亚基以及 CCCs 的 Western 印迹分析。
与对照组相比，P14 时 FS 的成年 FAST 大鼠的运动图更大，刺激阈值更低，而 P10 时 FS 的成年 LE 大鼠的运动图刺激阈值显著降低，但大小相似。与 P14 LE 大鼠相比，P14 时 FS 的成年 LE 大鼠的感觉运动皮层中的运动图大小或刺激阈值没有差异。与 P14 LE 大鼠相比，P10 LE 和 P14 FAST 大鼠的感觉运动皮层中的 GABA(A)受体α1 亚基水平较低，α2 亚基水平较高，NKCC1/KCC2 比值较高。此外，与 P14 LE 大鼠相比，P14 FAST 大鼠的感觉运动皮层中的 GluR2 和 NR2A 受体亚基水平较低。
单次婴儿 FS 会对年轻个体和潜在易发性癫痫的皮质重组产生长期影响。这些变化可能与年轻或遗传性易发性大鼠的新皮层兴奋性增加有关，这表明其 GABA 能和 CCC 系统不成熟。鉴于儿童 FS 的发生率较高，了解年龄和遗传易感性如何可能导致这些事件的长期后果将非常重要。
