Novel role of the nociceptin system as a regulator of glutamate transporter expression in developing astrocytes

Our previous results showed that oligodendrocyte development is regulated by both nociceptin and its G‐protein coupled receptor, the nociceptin/orphanin FQ receptor (NOR). The present in vitro and in vivo findings show that nociceptin plays a crucial conserved role regulating the levels of the glutamate/aspartate transporter GLAST/EAAT1 in both human and rodent brain astrocytes. This nociceptin‐mediated response takes place during a critical developmental window that coincides with the early stages of astrocyte maturation. GLAST/EAAT1 upregulation by nociceptin is mediated by NOR and the downstream participation of a complex signaling cascade that involves the interaction of several kinase systems, including PI‐3K/AKT, mTOR, and JAK. Because GLAST is the main glutamate transporter during brain maturation, these novel findings suggest that nociceptin plays a crucial role in regulating the function of early astrocytes and their capacity to support glutamate homeostasis in the developing brain. Main Points Nociceptin increases expression of the glutamate transporter GLAST in human and rat astrocytes. This effect is restricted to a critical maturational window, suggesting a role of nociceptin in controlling glutamate homeostasis in the developing brain.