Peripheral viral challenge elevates extracellular glutamate in the hippocampus leading to seizure hypersusceptibility.
Peripheral viral challenge elevates extracellular glutamate in the hippocampus leading to seizure hypersusceptibility.
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DOI：
10.1111/jnc.13999
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发表时间：
2017-05
影响因子：
4.7
通讯作者：
Reed MN
中科院分区：
文献类型：
--
作者：
Hunsberger HC;Konat GW;Reed MN
外周病毒感染增加易感个体的癫痫发作倾向和强度。我们通过证明腹膜内（i. p.）注射病毒模拟物聚肌苷酸-聚胞苷酸（PIC）诱导对红藻氨酸（KA）诱导的癫痫发作的持续过敏性。我们已经进一步证明，PIC挑战鲁棒地增加了紧张性细胞外谷氨酸和海马神经元兴奋性的水平。本研究旨在确定强直性谷氨酸与PIC激发后癫痫发作易感性之间的关系。简言之，将谷氨酸敏感微电极永久植入8周龄雌性C57 BL/6小鼠的CA 1中。在3天恢复期后，通过腹腔注射12 mg/kg PIC诱导APR，而盐水注射小鼠作为对照。在PIC激发后1、2、3和4天测量紧张性谷氨酸。PIC激发诱导24小时后测量的强直性谷氨酸水平增加约4倍。在四天内，这些水平逐渐下降到基线值。在PIC激发后24小时，小鼠的特征是累积癫痫发作评分增加约3倍，并且通过皮下（s.c.）注射12 mg/kg KA。癫痫发作评分与癫痫发作前的强直性谷氨酸呈正相关。此外，癫痫发作导致了一个深刻的（76%）升高细胞外谷氨酸在PIC挑战，但不是盐水注射小鼠的CA 1。我们的研究结果暗示细胞外谷氨酸的增加作为介导的癫痫发作过敏性周围病毒的挑战。腹膜内注射病毒模拟物PIC导致海马中细胞外（强直性）谷氨酸的强烈升高。在这里，我们发现，强直性谷氨酸水平正相关的易感性红藻氨酸（KA）诱导的癫痫发作。PIC激发引起的强直性谷氨酸升高可能是海马神经元过度兴奋的结果。此外，海马实质内的炎症环境可能直接增加了紧张性谷氨酸水平。紧张性谷氨酸可能通过突触外受体增强和/或维持神经元兴奋性。我们认为，神经元过度兴奋和升高的强直性谷氨酸都有助于癫痫发作易感性的加剧。
Peripheral viral infections increase seizure propensity and intensity in susceptible individuals. We have modeled this comorbidity by demonstrating that the acute phase response (APR) instigated by an intraperitoneal (i.p.) injection of a viral mimetic, polyinosinic-polycytidylic acid (PIC), induces protracted hypersusceptibility to kainic-acid (KA)-induced seizures. We have further demonstrated that PIC challenge robustly increases the level of tonic extracellular glutamate and neuronal excitability in the hippocampus. The present study was undertaken to determine a relationship between tonic glutamate and seizure susceptibility following PIC challenge. Briefly, glutamate-sensing microelectrodes were permanently implanted into the CA1 of eight-week old female C57BL/6 mice. Following a three day recovery, APR was induced by i.p. injection of 12 mg/kg of PIC, while saline-injected mice served as controls. Tonic glutamate was measured at 1, 2, 3 and 4 days after PIC challenge. PIC challenge induced an approximately 4-fold increase in tonic glutamate levels measured after 24 h. The levels gradually declined to the baseline values within four days. 24 h after PIC challenge, the mice featured an approximately 3-fold increase in cumulative seizure scores and 2-fold increase in the duration of status epilepticus induced by subcutaneous (s.c.) injection of 12 mg/kg of KA. Seizure scores positively correlated with pre-seizure tonic glutamate. Moreover, seizures resulted in a profound (76%) elevation of extracellular glutamate in the CA1 of PIC-challenged but not saline-injected mice. Our results implicate the increase of extracellular glutamate as a mediator of seizure hypersusceptibility induced by peripheral viral challenge. Intraperitoneal injection of a viral mimetic, PIC, results in a robust elevation of extracellular (tonic) glutamate in the hippocampus. Here, we showed that tonic glutamate levels positively correlate with the susceptibility to kainic acid (KA)-induced seizures. The elevation of tonic glutamate by PIC challenge likely results from the hyperexcitability of hippocampal neurons. In addition, tonic glutamate level might be increased directly by inflammatory milieu in the hippocampal parenchyma. Tonic glutamate enhances and/or sustains neuronal excitability likely through extrasynaptic receptors. We posit that both, neuronal hyperexcitability and elevated tonic glutamate contribute to the exacerbation of seizure susceptibility.