Metalloneurochemistry and the Pierian Spring: ‘Shallow Draughts Intoxicate the Brain’

Abstract

Metal ions perform critical and diverse functions in nervous system physiology and pathology. The field of metalloneurochemistry aims to understand the mechanistic bases for these varied roles at the molecular level. Here, we review several areas of research that illustrate progress toward achieving this ambitious goal and identify key challenges for the future. We examine the use of lithium as a mood stabilizer, the roles of mobile zinc and copper in the synapse, the interplay of nitric oxide and metals in retrograde signaling, and the regulation of iron homeostasis in the brain. These topics were chosen to demonstrate not only the breadth of the field, but also to highlight opportunities for discovery by studying such complex systems in greater detail. We are beginning to uncover the principles by which receptors and transmitters utilize metal ions to modulate neurotransmission. These advances have revealed exciting new insights into the intricate mechanisms that give rise to learning, memory, and sensory perception, while opening many new avenues for further exploration.

Bioinorganic Life and Neural Activity: Toward a Chemistry of Consciousness?

“…It is no coincidence that this unique biology is underpinned by unique chemistry, where this organ accumulates more elements at higher concentrations than any other part of the body. 4–6 For example, redox metals like copper and iron are particularly important owing to the high metabolic and signaling load of brain tissue, representing just 2% of body weight but 20% of body oxygen consumption. 4,7 As such, the bioinorganic chemistry of the brain offers a rich area for discovery in the broadest of terms, and studying the contributions of metals to neural activity as a first step to finding the elusive chemistry of consciousness is the subject of this “Holy Grail” Commentary (Figure 1).…”

“…8,9 This emerging field complements the well-recognized roles of redox-inactive elements like calcium, zinc, potassium, and sodium as brain signals. 4–6…”

Zinc as a Neuromodulator in the Central Nervous System with a Focus on the Olfactory Bulb

“…Various tools for studying vesicular zinc have recently emerged. These include highly selective fluorescent probes that can be used to detect mobile zinc in live cells and tissues, different types of KO mice (e.g., ZnT3 KO mice lacking vesicular zinc; Palmiter et al, 1996 ; Cole et al, 1999 ), and various zinc chelators (Goldberg et al, 2016 ).…”

“…The exact quantity of vesicular zinc released into the synaptic cleft is unclear. The concentration of zinc in the synaptic cleft after an excitatory event is influenced by factors such as the number of zinc vesicles that fuse to the presynaptic membrane (Goldberg et al, 2016 ). Early studies suggested that extracellular zinc concentrations ranged from 10 to 300 μM following depolarization of neurons (Frederickson et al, 1983 ; Assaf and Chung, 1984 ; Howell et al, 1984 ; Xie and Smart, 1991 ).…”

“…However, synaptic concentrations of zinc could be greater given that the synaptic cleft comprises only part of the extracellular space. More recently, it has been estimated that peak zinc concentrations in the synaptic cleft following exocytosis range from 10 nM to >100 μM (Vogt et al, 2000 ; Ueno et al, 2002 ; Paoletti et al, 2009 ; Vergnano et al, 2014 ; Goldberg et al, 2016 ). Synaptic concentrations of zinc in the micromolar range are not unexpected since the synaptic concentrations of glutamate (Clements et al, 1992 ), GABA (Jones and Westbrook, 1995 ), and glycine (Beato, 2008 ) all exceed 1 mM.…”