Zinc. Metal. Number 30 on the periodic table. Twenty-fourth most abundant element on Earth. Common oxidation state of 2+.
Did you take your multivitamin today? Did it have zinc in it? Zinc is used to treat a wide variety of ailments from acne to the common cold, but did you also know it's important in memory formation? A new study lead by James McNamara M.D. of Duke University Medical Center shows that zinc can enhance communication between cells, particularly in the hippocampus, a center of memory formation. This data leads to the hypothesis that excessive enhancement mediated by zinc might occur in epilepsy and play a part in the severity of seizures. These findings could lead to developing new drugs for epilepsy.
High concentrations of zinc in synaptic vesicles was discovered in the 1950s and has perplexed neurobiologist ever since. These vesicles are colocalized with glutamatergic neurons of the hippocampus suggesting that zinc might be released and play a role in the plasticity of excitatory synapses. Efforts to determine zinc's function in these synapses has been difficult to determine because of previously available zinc chelators which were not specific for zinc and did not bind fast enough to remove zinc in the time scale of synaptic transmission. In the September issue of Neuron, a collaboration between Steve Lippard from MIT's Department of Chemistry and Duke University Medical Center has synthesized a novel zinc chelator. By using the chelator in mice, they found that zinc promotes presynaptic and inhibits postsynaptic long-term potentiaion in the mossy fiber-CA3 synapse.
The group began by creating a new zinc chelator, called ZX1, that binds zinc fast and has a higher specificity for zinc versus calcium or magnesium than other chelators. By using ZX1 to remove zinc from the synapse as soon as it was released, they were able to look at what happens to long-term potentiation without zinc. Using ZX1 in the hippocampus of mice, the data found that ZX1 inhibited mossy fiber-LTP. Mossy fiber LTP is NMDA independent, working by other mechanisms based in the presynaptic cell. The group also did experiments on ZnT3 null mutant mice, which lack the transporter that packages zinc into vesicles. These experiments were surprising because they saw that, as previously seen in wild type mice, zinc enhanced the presynaptic mf-LTP, but zinc actually inhibited postsynaptic mf-LTP.
Overall, zinc seems to modify the circuits related to learning and memory, but don't start gobbling down zinc supplements just yet. Zinc is a trace metal in biology, and certainly too much can be toxic. Knowing the molecular mechanisms of synaptic plasticity and excitability is an important step in treating diseases such as epilepsy, but as of yet there is no established beneficial level of zinc. In fact, too much zinc might increase the enhancement of these synapses, leading to more severe seizures. A new drug might act like ZX1 to bind zinc and remove it from the synapse, in order to reduce the enhancement of the excitatory synapse.
Enhui Pan, Xiao-an Zhang, Zhen Huang, Artur Krezel, Min Zhao, Christine E. Tinberg, Stephen J. Lippard, James O. McNamara, Vesicular Zinc Promotes Presynaptic and Inhibits Postsynaptic Long-Term Potentiation of Mossy Fiber-CA3 Synapse, Neuron, Volume 71, Issue 6, 22 September 2011, Pages 1116-1126, ISSN 0896-6273, 10.1016/j.neuron.2011.07.019.
Less in depth summary of paper: