Early alterations of AMPA receptors mediate synaptic potentiation induced by neonatal seizures.
Early alterations of AMPA receptors mediate synaptic potentiation induced by neonatal seizures.
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DOI：
10.1523/jneurosci.1734-08.2008
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发表时间：
2008-08-06
期刊：
影响因子：
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通讯作者：
Jensen FE
中科院分区：
文献类型：
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作者：
Rakhade SN;Zhou C;Aujla PK;Fishman R;Sucher NJ;Jensen FE
新生儿期癫痫发作的发病率最高，新生儿癫痫发作会导致癫痫倾向和长期认知缺陷。在这里，我们确定了潜在的机制，阐明了关键作用的AMPA受体（AMPAR）在癫痫发生在这一关键时期，在发育中的大脑。在新生儿癫痫发作的啮齿动物模型中，我们先前已经表明，在癫痫发作后48小时内给予AMPAR拮抗剂可以防止癫痫发作易感性和癫痫引起的神经元损伤的长期增加。缺氧诱导的癫痫发作在出生后第10天的大鼠诱导快速和可逆的AMPAR信号类似的变化，涉及在体外突触增强模型。缺氧性癫痫发作后取出的海马脑片表现出AMPAR介导的突触电流增强，包括自发和微型EPSC的振幅和频率增加以及突触效能增加。这种增加的兴奋性在时间上与GluR 1 S845/S831和GluR 2 S880位点磷酸化的快速增加以及介导这些AMPAR亚基磷酸化的蛋白激酶CaMKII（钙/钙调蛋白依赖性蛋白激酶II）、PKA和PKC的活性增加相关。癫痫发作后给予AMPAR拮抗剂NBQX（2，3-二羟基-6-硝基-7-磺酰基-苯并[f]喹喔啉）、托吡酯或GYKI-53773 [（1）-1-（4-氨基苯基）-3-乙酰基-4-甲基-7，8-亚甲二氧基-3，4-二氢-5H-2，3-苯并二氮杂卓]减弱了AMPAR增强、磷酸化和激酶激活，并防止了体内癫痫发作易感性的同时增加。因此，含AMPAR的突触的增强是癫痫发生的可逆的早期步骤，其在高度易癫痫的发育中的大脑中提供了新的治疗靶点。
The highest incidence of seizures during lifetime is found in the neonatal period and neonatal seizures lead to a propensity for epilepsy and long-term cognitive deficits. Here, we identify potential mechanisms that elucidate a critical role for AMPA receptors (AMPARs) in epileptogenesis during this critical period in the developing brain. In a rodent model of neonatal seizures, we have shown previously that administration of antagonists of the AMPARs during the 48 h after seizures prevents long-term increases in seizure susceptibility and seizure-induced neuronal injury. Hypoxia-induced seizures in postnatal day 10 rats induce rapid and reversible alterations in AMPAR signaling resembling changes implicated previously in models of synaptic potentiation in vitro. Hippocampal slices removed after hypoxic seizures exhibited potentiation of AMPAR-mediated synaptic currents, including an increase in the amplitude and frequency of spontaneous and miniature EPSCs as well as increased synaptic potency. This increased excitability was temporally associated with a rapid increase in phosphorylation at GluR1 S845/S831 and GluR2 S880 sites and increased activity of the protein kinases CaMKII (calcium/calmodulin-dependent protein kinase II), PKA, and PKC, which mediate the phosphorylation of these AMPAR subunits. Post-seizure administration of AMPAR antagonists NBQX (2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline), topiramate, or GYKI-53773 [(1)-1-(4-aminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine] attenuated the AMPAR potentiation, phosphorylation, and kinase activation and prevented the concurrent increase in in vivo seizure susceptibility. Thus, the potentiation of AMPAR-containing synapses is a reversible, early step in epileptogenesis that offers a novel therapeutic target in the highly seizure-prone developing brain.