Is Zinc a New Class of Neurotransmitter? A Presynaptic Model

Using the zinc specific intracellular indicator Zinpyr-1, we describe a new technique for observing the presynaptic uptake and release of zinc in the MF→CA3 circuit of the mammalian hippocampus. Our model is sensitive to the addition of exogenous Zn²⁺ and responds to K⁺ depolarization, providing evidence for the synaptic release and reuptake of vesicular Zn²⁺. We also examine the sensitivity of our technique to vesicular Zn²⁺ depletion by metal chelators. Finally, the model we describe presents new and novel evidence for the translocation of synaptically released zinc to the postsynaptic cell bodies. Our results provide compelling supporting evidence for Zn²⁺ as a substance that undergoes release as a neurotransmitter and should be of interest to researchers investigating the physiological role of Zn²⁺ in such models as LTP and ischemia. Finally, the data we provide support the hypothesis that Zn²⁺ is a representative of a new class of neurotransmitters made up of divalent metal cations, functionally unique in their ability to translocate across the synaptic cleft and into the postsynaptic cell body to affect cellular signaling pathways.