Zn2+ ions:: Modulators of excitatory and inhibitory synaptic activity

The role of Zn2+ in the CNS has remained enigmatic for several decades. This divalent cation is accumulated by specific neurons into synaptic vesicles and can be released by stimulation in a Ca2+-dependent manner. Using Zn2+, fluorophores, radiolabeled Zn2+, and selective chelators, the location of this ion and its release pattern have been established across the brain. Given the distribution and possible release under physiological conditions, Zn2+, has the potential to act as a modulator of both excitatory and inhibitory neurotransmission. Excitatory N-methyl-D-aspartate (NMDA) receptors are directly inhibited by Zn2+, whereas non-NMDA receptors appear relatively unaffected. In contrast, inhibitory transmission mediated via GABA, receptors can be potentiated via a presynaptic mechanism, influencing transmitter release; however, although some tonic GABAergic inhibition may be suppressed by Zn2+, most synaptic GABA receptors are unlikely to be modulated directly by this cation. In the spinal cord, glycinergic transmission may also be affected by Zn2+, causing potentiation. Recently, the penetration of synaptically released Zn2+, into neurons suggests that this ion has the potential to act as a direct transmitter, by affecting postsynaptic signaling pathways. Taken overall, present studies are broadly supportive of a neuromodulatory role for Zn2+ at specific excitatory and inhibitory synapses.