The actions of synaptically released zinc at hippocampal mossy fiber synapses

Zn2+ is present at high concentrations in the synaptic Vesicles of hippocam pal mossy fibers. We have used Zn2+ chelators and the mocha mutant mouse to address the physiological role of Zn2+ in this pathway. Zn2+ is not involv ed in the unique presynaptic plasticities observed at mossy fiber synapses but is coreleased with glutamate from these synapses, both spontaneously an d with electrical stimulation, where it exerts a strong modulatory effect o n the NMDA receptors. Zn2+ tonically occupies the high-affinity binding sit e of NMDA receptors at mossy fiber synapses, whereas the lower affinity vol tage-dependent Zn2+ binding site is occupied during action potential driven -release. We conclude that Zn2+ is a modulatory neurotransmitter released f rom mossy fiber synapses and plays an important role in shaping the NMDA re ceptor response at these synapses.