A role for zinc signaling, via ZnR/GPR39, in neuronal development

Zinc is an essential ion (Zn²⁺) that specifically accumulates in synaptic vesicles, most prominently in the mossy fiber terminals of the dentate gyrus. Accumulation of the synaptic Zn²⁺, is developmentally regulated, together with numerous Zn²⁺ transporters that facilitate its spatial localization. Links between zinc deficiency and cognitive function or seizure underline the importance of this metal ion. Nevertheless, the molecular pathways that Zn²⁺ activates were unclear for many years. We showed that synaptic Zn²⁺ activates a distinct target that is a Gq-coupled zinc sensing receptor, ZnR/GPR39. We show that release of synaptic Zn²⁺ triggers ZnR/GPR39-dependent Ca²⁺ signaling leading to activation of the mitogen activated kinase (MAPK) and AKT pathways, which are involved in neuronal survival and growth. In developing neurons in culture, we show that loss of ZnR/GPR39 affects the growth of neurites. Activation of ZnR/GPR39 also results in regulation of the K⁺/Cl^- co-transporter KCC2, and upregulation of the inhibitory tone, thereby reducing seizure. In the current study, we asked whether changes in neurogenesis in the dentate gyrus region, following seizure activity and accumulation of Zn²⁺ in the recurrent fibers, are mediated by ZnR/GPR39. Surprisingly, our results indicate that ZnR/GPR39 KO mice show increased numbers of newborn cells in the dentate gyrus following seizure. Altogether, our data supports an important role for ZnR/GPR39 in regulating neurogenesis and development of neurons.