Unraveling the role of zinc in memory

Abstract

Dietary zinc deficiency has been associated with memory impairment but the mechanisms underlying this effect remain unclear. The divalent cation zinc is one of the most abundant trace elements in the body and plays myriad functional roles (1). Although the vast majority of zinc is tightly bound to proteins, a pool of zinc in the mammalian forebrain is selectively stored in and released from glutamatergic neurons. This chelatable zinc is sequestered in synaptic vesicles and coreleased with glutamate during neuronal activity. Synaptically released zinc has the potential to interact with and modulate many different synaptic targets, including glutamate receptors and voltage-gated channels (2). Zinc can also modulate synaptic plasticity. The ability of zinc to modulate both ion channels and synaptic plasticity predicts that it plays a key role in learning and memory. This prediction was previously tested using mice in which the zinc transporter-3 (ZnT3) had been genetically deleted. ZnT3 is essential for loading zinc into synaptic vesicles (3). Targeted deletion of this transporter ablates vesicular zinc uptake and synaptic release of zinc and causes zinc in the forebrain to fall to undetectable levels (4). However, despite lacking chelatable zinc, ZnT3 KO mice did not exhibit impairments in spatial learning, memory, or sensorimotor functions (5). These findings suggested that vesicular zinc (and hence, ZnT3) was not essential for cognitive function. However, recent studies have forced a rethinking of the role of zinc in cognition. In particular, detailed examination has now revealed that ZnT3 KO mice exhibit impaired fear memory (6) as well as accelerated aging related decline of spatial memory (7). Despite these advances, the functional role of synaptic zinc in learning and memory remains largely a mystery. In PNAS, Sindreu et al. (8) provide a compelling and thorough study demonstrating an essential role for ZnT3 and thus vesicular zinc …