The subfornical organ (SFO) is a sensory circumventricular organ, lacking a proper blood-brain barrier. Neurons of the SFO are exposed directly to the ionic environment and circulating signaling molecules in the plasma, providing a unique window for communication of physiological status from the periphery to the central nervous system (CNS). The SFO is recognized as a key site for hydromineral balance, cardiovascular regulation and energy homeostasis. Neuropeptide Y (NPY) is a potent stimulator of food intake when released centrally, and has well-documented pressor effects when released peripherally. It has been demonstrated that the SFO expresses NPY receptors, however the effects of NPY on SFO neurons has never been investigated. The aim of this study was to determine the effects of NPY on the electrophysiological properties of SFO neurons dissociated from Sprague Dawley rats. Using whole cell patch clamp techniques in the current-clamp configuration, we report that 300 nM NPY caused 16% of SFO neurons to depolarize and 26% to hyperpolarize. The remaining neurons were insensitive to NPY. These effects were dose-dependent with a combined EC50 of 3.7 nM. Specific NPY receptor antagonists were applied, suggesting that the Y5 receptor predominately elicited a hyperpolarizing effect, while the Y1 receptor had a mixed response that was predominately hyperpolarizing, and the Y2 receptor had a mixed response that was predominately depolarizing. Using the voltage-clamp configuration, it was also observed that NPY caused an increase in the voltage-gated K+ current density as well as a shift in membrane activation of the persistent Na+ current, mediating the hyperpolarizing and depolarizing effects, respectively. These findings indicate that NPY elicits electrophysiological changes on SFO neurons, suggesting that the SFO is a key site of action for NPY in mediating energy regulation and/or cardiovascular output. / February 2017