Sechenov Institute of Evolutionary Physiology and Biochemistry of RAS, 44, Toreza Prospekt, 194223 Saint Petersburg, Russia.
Int J Mol Sci. 2021 Jul 30;22(15):8218. doi: 10.3390/ijms22158218.
Febrile seizures (FSs) in early life are significant risk factors of neurological disorders and cognitive impairment in later life. However, existing data about the impact of FSs on the developing brain are conflicting. We aimed to investigate morphological and functional changes in the hippocampus of young rats exposed to hyperthermia-induced seizures at postnatal day 10. We found that FSs led to a slight morphological disturbance. The cell numbers decreased by 10% in the CA1 and hilus but did not reduce in the CA3 or dentate gyrus areas. In contrast, functional impairments were robust. Long-term potentiation (LTP) in CA3-CA1 synapses was strongly reduced, which we attribute to the insufficient activity of N-methyl-D-aspartate receptors (NMDARs). Using whole-cell recordings, we found higher desensitization of NMDAR currents in the FS group. Since the desensitization of NMDARs depends on subunit composition, we analyzed NMDAR current decays and gene expression of subunits, which revealed no differences between control and FS rats. We suggest that an increased desensitization is due to insufficient activation of the glycine site of NMDARs, as the application of D-serine, the glycine site agonist, allows the restoration of LTP to a control value. Our results reveal a new molecular mechanism of FS impact on the developing brain.
热性惊厥（FS）是生命早期发生神经系统疾病和认知障碍的重要危险因素。然而，目前关于 FS 对发育中大脑影响的数据存在矛盾。我们旨在研究在出生后第 10 天暴露于高热诱导的惊厥的年轻大鼠海马体的形态和功能变化。我们发现 FS 导致了轻微的形态紊乱。CA1 和齿状回区的细胞数量减少了 10%，但 CA3 或齿状回区的细胞数量没有减少。相比之下，功能损伤更明显。CA3-CA1 突触的长时程增强（LTP）显著降低，我们认为这是由于 N-甲基-D-天冬氨酸受体（NMDAR）的活性不足所致。通过全细胞膜片钳记录，我们发现 FS 组的 NMDAR 电流的脱敏作用增强。由于 NMDAR 的脱敏作用取决于亚基组成，我们分析了 NMDAR 电流衰减和亚基的基因表达，结果发现对照组和 FS 组之间没有差异。我们认为，增加的脱敏作用是由于 NMDAR 甘氨酸位点的激活不足所致，因为 NMDAR 甘氨酸位点激动剂 D-丝氨酸的应用可以使 LTP 恢复到对照值。我们的结果揭示了 FS 对发育中大脑影响的新分子机制。
