Prostaglandin E₂ depresses GABA release onto parvocellular neuroendocrine neurones in the paraventricular nucleus of the hypothalamus via presynaptic receptors.

Inflammation-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis and the ensuing release of anti-inflammatory glucocorticoids are critical for the fine-tuning of the inflammatory response. This immune-induced neuroendocrine response is in large part mediated by prostaglandin E₂ (PGE₂ ), the central actions of which ultimately translate into the excitation of parvocellular neuroendocrine cells (PNCs) in the hypothalamic paraventricular nucleus. However, the neuronal mechanisms by which PGE₂ excites PNCs remain incompletely understood. In the present study, we report that PGE₂ potently depresses GABAergic inhibitory synaptic transmission onto PNCs. Using whole-cell patch clamp recordings obtained from PNCs in ex vivo hypothalamic slices from rats, we found that bath application of PGE₂ (0.01-100 μmol L^-1 ) concentration-dependently decreased the amplitude of evoked inhibitory postsynaptic currents (eIPSCs) with maximum effects at 10 μmol L^-1 . The PGE₂ -mediated depression of eIPSCs had a rapid onset and was long-lasting, and also was accompanied by an increase in paired pulse ratio. In addition, PGE₂ decreased the frequency but not the amplitude of both spontaneous IPSCs and miniature IPSCs. These results collectively indicate that PGE₂ acts at a presynaptic locus to decrease the probability of GABA release. Using pharmacological approaches, we also demonstrated that the EP3 subtype of the PGE₂ receptor mediated the actions of PGE₂ on GABA synapses. Taken together, our results show that PGE₂ , via actions of presynaptic EP3 receptors, potently depresses GABA release onto PNCs, providing a plausible mechanism for the disinhibition of HPA axis output during inflammation.

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