P2X7-dependent constitutive Interleukin-1β release from pyramidal neurons of the normal mouse hippocampus: Evidence for a role in maintenance of the innate seizure threshold

Disruption of Interleukin-1 beta (IL-1 beta) signaling sensitized mice to convulsant stimuli, suggesting that this quin-tessential cytokine of the innate immune system contributes to maintenance of the innate seizure threshold (ST). However, much remains unknown about where and how IL-1 beta secretion occurs in the normal brain. This study examined the possibility that neurons of the hippocampus are key sources of constitutive IL-1 beta secretion and that the release from these cells is dependent on the purinoceptor, P2X7. It was posited that treatment with the P2X7 antagonist, JNJ-47965567 (JNJ), would cause IL-1 beta to accumulate in cells that produce it, and consequently, lower the ST. No IL-1 beta immunoreactivity was detected in any region of the hippocampal formation of mice treated with the JNJ vehicle, Sulfobutylether-beta-cyclodextrin. In contrast, prominent immunoreactivity was discovered in the pyramidal neurons of the CA3 region 60 min after treatment with the P2X7 antagonist. Lower levels were found in CA1 neurons, and no immunoreactivity was detected in granule cells of the dentate gyrus. JNJ also increased IL-1 beta immunoreactivity in the cell bodies of hippocampal neurons in culture. Interestingly, JNJ potentiated bicuculline-induced Fos and COX-2 mRNA expression in the cultures and this was blocked by an NMDA receptor antagonist. Moreover, pentylenetetrazole-induced seizure severity and incidence of convulsions were increased in mice treated with JNJ and this resembled that observed with IL-1 signaling-deficient mice. Overall, the results from this study support the notion that constitutive P2X7-dependent IL-1 beta release from hippocampal pyramidal neurons contributes to maintenance of the ST in the normal brain, perhaps by modulating neuronal excitability. These findings may have implications for epilepsy, a brain disorder in which the ST is compromised.