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Zn2+ Ions: Modulators of Excitatory and Inhibitory Synaptic Activity

Department of Pharmacology, University College London, t.smart{at}ucl.ac.uk

Alastair M. Hosie

Department of Pharmacology, University College London

Paul S. Miller

Department of Pharmacology, University College London

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_Areceptors 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.

Key Words: Zinc • Synaptic transmission • GABA • Glutamate

The Neuroscientist, Vol. 10, No. 5, 432-442 (2004)
DOI: 10.1177/1073858404263463


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