Interleukin-1β induces hyperpolarization and modulates synaptic inhibition in preoptic and anterior hypothalamic neurons

Most of the inflammatory effects of the cytokine interleukin 1β (IL-1β) are mediated by induction of cyclooxygenase (COX)2 and the subsequent synthesis and release of prostaglandin E2. This transcription-dependent process takes 45–60 min, but IL-1β, a well-characterized endogenous pyrogen also exerts faster neuronal actions in the preoptic area/anterior hypothalamus. Here, we have studied the fast (1–3 min) signaling by IL-1β using whole-cell patch clamp recordings in preoptic area/anterior hypothalamus neurons. Exposure to IL-1β (0.1–1 nM) hyperpolarized a subset (∼20%) of preoptic area/anterior hypothalamus neurons, decreased their input resistance and reduced their firing rate. These effects were associated with an increased frequency of bicuculline-sensitive spontaneous inhibitory postsynaptic currents and putative miniature inhibitory postsynaptic currents, strongly suggesting a presynaptic mechanism of action. These effects require the type 1 interleukin 1 receptor (IL-1R1), and the adapter protein myeloid differentiation primary response protein (MyD88), since they were not observed in cultures obtained from IL-1R1 (−/−) or from MyD88 (−/−) mice. Ceramide, a second messenger of the IL-1R1–dependent fast signaling cascade, is produced by IL-1R1–MyD88–mediated activation of the neutral sphingomyelinase. C2-ceramide, its cell penetrating analog, also increased the frequency of miniature inhibitory postsynaptic currents in a subset of cells. Both IL-1β and ceramide reduced the delayed rectifier and the A-type K+ currents in preoptic area/anterior hypothalamus neurons. The latter effect may account in part for the increased spontaneous inhibitory postsynaptic current frequency as suggested by experiments with the A-type K+ channel blockers 4-aminopyridine. Taken together our data suggest that IL-1β inhibits the activity of preoptic area/anterior hypothalamus neurons by increasing the presynaptic release of GABA.