Zinc is present in synaptic vesicles and can be detected in synaptic regions. Various proteins that function in synaptic transmission (neurotransmitter receptors and transporters) are modulated by zinc, including glycine receptors (GlyRs), which are potentiated at low concentrations of zinc and inhibited by high concentrations of zinc. On the basis of previous experiments in which residues critical for zinc modulation had been determined, Hirzel et al . created knockin mice containing a mutation in the gene encoding the GlyR α1 subunit [ Glra1 (D80A)] in which zinc was no longer able to potentiate GlyR function. The mutant mice showed a neuromotor phenotype very similar to a human disorder called hyperekplexia; the mouse version includes increased acoustic startle reflex, altered visual signaling, inducible tremor, and altered gait. Spinal neurons cultured from wild-type and mutant mice showed that glycine responsiveness in the absence of added Zn 2+ was unchanged. However, neurons from the mutant mice showed decreased potentiation of glycine-mediated currents in the presence of 5 μM Zn 2+ without any impairment of inhibition of glycine-mediated currents in the presence of 100 μM Zn 2+ . In spinal cord cultures, application of 5 μM Zn 2+ increased the amplitude of miniature inhibitory postsynaptic currents (mIPSCs) in the wild-type cultures but decreased the amplitude of the mIPSCs in the mutant cultures. Slice preparations containing hypoglossal motoneurons did not exhibit altered IPSCs in response to exogenous Zn 2+ , suggesting that the slices contained sufficient free Zn 2+ to maximally potentiate GlyR-mediated currents. However, if free Zn 2+ was chelated, the amplitude of the IPSCs decreased in the wild-type slices and addition of 5 μM Zn 2+ restored the IPSC amplitude. Chelation of Zn 2+ had no effect on slices from the mutant mice. The role of zinc in synaptic signaling has been controversial, but even the skeptics should find that these results provide compelling evidence for an important neuromodulatory role for zinc in inhibitory synaptic transmission (see Kay et al .). Readers are invited to discuss this article and the general topic of zinc in cell signaling in the open forum "Questions and Controversies in Zinc Signaling" (see Related Resources). K. Hirzel, U. Müller, A. T. Latal, S. Hülsmann, J. Grudzinska, M. W. Seeliger, H. Betz, B. Laube, Hyperekplexia phenotype of glycine receptor α1 subunit mutant mice identifies Zn 2+ as an essential endogenous modulator of glycinergic neurotransmission. Neuron 52 , 679-690 (2006). [PubMed] A. R. Kay, J. Neyton, P. Paoletti, A startling role for synaptic zinc. Neuron 52 , 572-574 (2006). [PubMed]