Document Type

Article

Disciplines

Medicine and Health Sciences | Neuroscience and Neurobiology

Abstract

Copper (Cu) is an essential metal present at high levels in the CNS. Its role as a co-factor in mitochondrial ATP production and in other essential cuproenzymes is well defined. Menkes and Wilson’s diseases are severe neurodegenerative conditions that demonstrate the importance of Cu transport into the secretory pathway. Brain levels of Cu, which is almost entirely protein bound, exceed extracellular levels by more than a hundred-fold. Cu stored in the secretory pathway is released in a Ca2+-dependent manner and can transiently reach concentrations over 100 µM at synapses. The ability of low µM levels of Cu to bind to and modulate the function of γ-aminobutyric acid type A (GABAA) receptors, N-methyl-D-aspartate (NMDA) receptors and voltage-gated Ca2+ channels contributes to its effects on synaptic transmission. Cu also binds to amyloid precursor protein and prion protein; both proteins are found at synapses and brain Cu homeostasis is disrupted in mice lacking either protein. Especially intriguing is the ability of Cu to affect AMP-activated protein kinase (AMPK), a monitor of cellular energy status. Despite this, few investigators have examined the direct effects of Cu on synaptic transmission and plasticity. Although the variability of results demonstrates complex influences of Cu that are highly method-sensitive, these studies nevertheless strongly support important roles for endogenous Cu and new roles for Cu-binding proteins in synaptic function/plasticity and behavior. Further study of the many roles of Cu in nervous system function will reveal targets for intervention in other diseases in which Cu homeostasis is disrupted.

Comments

J Neurosci Res. Author manuscript; available in PMC 2014 February 17. Published in final edited form as: J Neurosci Res. 2013 January; 91(1): 2–19. Published online 2012 November 1. doi: 10.1002/jnr.23143 PMCID: PMC3926505 NIHMSID: NIHMS553406

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