Title

Peripherally restricted viral challenge elevates extracellular glutamate and enhances synaptic transmission in the hippocampus

Document Type

Article

Publication Date

7-1-2016

Abstract

Peripheral infections increase the propensity and severity of seizures in susceptible populations. We have previously shown that intraperitoneal (i.p.) injection of a viral mimic, polyinosinic-polycytidylic acid (PIC), elicits hypersusceptibility of mice to kainic acid (KA)-induced seizures. The present study was undertaken to determine whether this seizure hypersusceptibility entails alterations in glutamate signaling. Female C57BL/6 mice were i.p. injected with PIC, and after 24 hours, glutamate homeostasis in the hippocampus was monitored using the enzyme-based microelectrode arrays. PIC challenge robustly increased the level of resting extracellular glutamate. While presynaptic potassium-evoked glutamate release was not affected, glutamate uptake was profoundly impaired and non-vesicular glutamate release was augmented, indicating functional alterations of astrocytes. Electrophysiological examination of hippocampal slices from PIC-challenged mice revealed a several fold increase in the basal synaptic transmission as compared to control slices. PIC challenge also increased the probability of presynaptic glutamate release as seen from a reduction of paired-pulse facilitation (PPF) and synaptic plasticity as seen from an enhancement of long-term potentiation (LTP). Altogether, our results implicate a dysregulation of astrocytic glutamate metabolism and an alteration of excitatory synaptic transmission as the underlying mechanism for the development of hippocampal hyperexcitability, and consequently seizure hypersusceptibility following peripheral PIC challenge.

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