Peripheral viral challenge elevates extracellular glutamate in the hippocampus leading to seizure hypersusceptibility

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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.