Modulation of extrasynaptic NMDA receptors by synaptic and tonic zinc

Significance As an essential element for living organisms, zinc is a cofactor in many enzymes and regulatory proteins. After the surprising discovery of mobile zinc in synaptic vesicles throughout many areas of the brain, numerous investigators have studied its possible roles during neurotransmission. Nonetheless, knowledge of the physiology of zinc at the synapse is still in its infancy. Here, we show that synaptic and tonic zinc inhibit extrasynaptic NMDA receptors (NMDARs), which are widely distributed in the CNS and are important for normal and pathological excitatory signaling. Our work indicates that this newly discovered interaction between zinc and extrasynaptic NMDARs can provide a general mechanism for controlling neuronal excitability in the CNS.