Department of Neurology, Division of Neuroscience, Children's Hospital, Boston, Massachusetts 02115, USA.
J Neurosci. 2011 Dec 14;31(50):18211-22. doi: 10.1523/JNEUROSCI.4838-11.2011.
Neonatal seizures can lead to epilepsy and long-term cognitive deficits into adulthood. Using a rodent model of the most common form of human neonatal seizures, hypoxia-induced seizures (HS), we aimed to determine whether these seizures modify long-term potentiation (LTP) and silent NMDAR-only synapses in hippocampal CA1. At 48-72 h after HS, electrophysiology and immunofluorescent confocal microscopy revealed a significant decrease in the incidence of silent synapses, and an increase in AMPARs at the synapses. Coincident with this decrease in silent synapses, there was an attenuation of LTP elicited by either tetanic stimulation of Schaffer collaterals or a pairing protocol, and persistent attenuation of LTP in slices removed in later adulthood after P10 HS. Furthermore, postseizure treatment in vivo with the AMPAR antagonist 2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline (NBQX) protected against the HS-induced depletion of silent synapses and preserved LTP. Thus, this study demonstrates a novel mechanism by which early life seizures could impair synaptic plasticity, suggesting a potential target for therapeutic strategies to prevent long-term cognitive deficits.
新生儿癫痫发作可导致癫痫和成年后长期认知缺陷。本研究使用最常见的人类新生儿癫痫发作缺氧诱导性癫痫发作(HS)的啮齿动物模型,旨在确定这些癫痫发作是否会改变海马 CA1 区的长时程增强(LTP)和沉默的 NMDAR 单突触。在 HS 后 48-72 小时,电生理学和免疫荧光共聚焦显微镜显示沉默突触的发生率显著降低,突触处 AMPAR 增加。与沉默突触减少相一致的是,无论是通过 Schaffer 侧支的强直刺激还是配对方案诱发的 LTP 均减弱,并且在 P10 HS 后的后期成年期取出的切片中 LTP 持续减弱。此外,体内用 AMPAR 拮抗剂 2,3-二羟基-6-硝基-7-磺酸基苯并[f]喹喔啉(NBQX)进行的 postseizure 治疗可防止 HS 引起的沉默突触耗竭并保留 LTP。因此,这项研究证明了新生儿期癫痫发作可能损害突触可塑性的新机制,提示了预防长期认知缺陷的治疗策略的潜在目标。