It is well established that the neuropeptide gonadotropin-releasing hormone (GnRH) regulates the secretion of pituitary gonadotropins. Evidence also suggests a neuromodulatory role for GnRH, yet its mechanism is unknown. It has recently been shown that in the medaka genome, the GnRH II and GnRH III genes reside adjoining the genes encoding protein tyrosine phosphatase alpha (PTPalpha) and PTP, respectively. Here we isolated and characterized PTPalpha and PTP in the medaka, and demonstrated using an in vitro medaka whole-brain culture system that GnRH downregulates the PTPalpha/PTP gene expression. This finding, together with the fact that PTPalpha/PTP regulate neuronal excitability through interacting with voltage-gated potassium channel, suggests that GnRH gene products would act as neuromodulators via downregulating their neighboring PTPalpha/PTP genes.