Zn2+ ions: modulators of excitatory and inhibitory synaptic activity

Neuroscientist. 2004 Oct;10(5):432-42. doi: 10.1177/1073858404263463.


The role of Zn(2+) 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 Ca(2+)-dependent manner. Using Zn(2+) fluorophores, radiolabeled Zn(2+), 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, Zn(2+) 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 Zn(2+), whereas non-NMDA receptors appear relatively unaffected. In contrast, inhibitory transmission mediated via GABA(A)receptors can be potentiated via a presynaptic mechanism, influencing transmitter release; however, although some tonic GABAergic inhibition may be suppressed by Zn(2+), most synaptic GABA receptors are unlikely to be modulated directly by this cation. In the spinal cord, glycinergic transmission may also be affected by Zn(2+) causing potentiation. Recently, the penetration of synaptically released Zn(2+) 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 Zn(2+) at specific excitatory and inhibitory synapses.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cations, Divalent / chemistry
  • Cations, Divalent / metabolism
  • Excitatory Postsynaptic Potentials / physiology*
  • Humans
  • Neural Inhibition / physiology*
  • Synapses / chemistry*
  • Synapses / metabolism*
  • Zinc / chemistry*
  • Zinc / metabolism
  • Zinc / physiology*


  • Cations, Divalent
  • Zinc