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The entorhinal cortex (EC) has long been regarded as a bidirectional gateway between higher cortical areas and the hippocampus.Orexins (hypocretins) are wake-promoting neuropeptides which are mainly produced by the neurons within the lateral hypothalamus.Orexin system includes two separate peptides orexin-A and orexin-B proteolytically derived from the same precursor protein and two specific G-protein-coupled receptors OX1R and OX2R.In the present study, we firstly investigated the electrophysiological effects of orexin-A on stellate neurons and pyramidal neurons in live brain slices of the EC using whole-cell patch-clamp recordings, and then observed signaling cascades triggering the ionic and synaptic mechanisms involved in orexin-A.The results show as follow: Orexin-A depolarizes stellate and pyramidal neurons in the superficial layers of EC through effects on K+ channels and non-selective cation conductances.The excitatory action of orexin-A involves OX 1Rs and PKC mediates both the inhibition of IK and activation of NSCC induced by orexin-A.Orexin-A enhances both excitatory and inhibitory synaptic transmissions in the superficial layers of EC via OX1Rs.In summury, the studies reported here provide evidence that the direct excitatory effects of orexin-A on principal neurons in the superficial layers of rat EC are mediated by the activation of OX1Rs and PKC signaling cascades, which inhibit sustained K+ current and activate NSCC.In addition, orexin-A enhances both excitatory and inhibitory synaptic transmissions in the EC via OX 1Rs.