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

Abstract

The olfactory bulb (OB) is central to the sense of smell, as it is the site of the first synaptic relay involved in the processing of odor information. Odor sensations are first transduced by olfactory sensory neurons (OSNs) before being transmitted, by way of the OB, to higher olfactory centers that mediate olfactory discrimination and perception. Zinc is a common trace element, and it is highly concentrated in the synaptic vesicles of subsets of glutamatergic neurons in some brain regions including the hippocampus and OB. In addition, zinc is contained in the synaptic vesicles of some glycinergic and GABAergic neurons. Thus, zinc released from synaptic vesicles is available to modulate synaptic transmission mediated by excitatory (e.g., N-methyl-D aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)) and inhibitory (e.g., gamma-aminobutyric acid (GABA), glycine) amino acid receptors. Furthermore, extracellular zinc can alter the excitability of neurons through effects on a variety of voltage-gated ion channels. Consistent with the notion that zinc acts as a regulator of neuronal activity, we and others have shown zinc modulation (inhibition and/or potentiation) of amino acid receptors and voltage-gated ion channels expressed by OB neurons. This review summarizes the locations and release of vesicular zinc in the central nervous system (CNS), including in the OB. It also summarizes the effects of zinc on various amino acid receptors and ion channels involved in regulating synaptic transmission and neuronal excitability, with a special emphasis on the actions of zinc as a neuromodulator in the OB. An understanding of how neuroactive substances such as zinc modulate receptors and ion channels expressed by OB neurons will increase our understanding of the roles that synaptic circuits in the OB play in odor information processing and transmission.

Comparison of Serum Trace Nutrient Concentrations in Epileptics Compared to Healthy Dogs

“…The epileptic dogs were divided into 3 subgroups: controlled epileptics (12), uncontrolled epileptics (42), and untreated epileptics (13). In the controlled epileptic group, there were 10 spayed females, 14 castrated males, and 3 intact males.…”

“…This is also the preferred binding site of endogenous neurosteroids, which are a topic of epilepsy research in humans due to their anti-convulsant effects (23). Of the free (non-protein bound) zinc in the brain, most of it is contained within synaptic vesicles, primarily in the hippocampus (a highly epileptogenic region) and the olfactory bulb (13). In a mouse model of kindling induced epilepsy, zinc was shown to significantly decrease the anti-convulsant effects of a synthetic neurosteroid, ganaxolone, when administered by infusion into the hippocampus (22).…”

Prospects of Zinc Supplementation in Autism Spectrum Disorders and Shankopathies Such as Phelan McDermid Syndrome

“…In addition, zinc has inhibitory effects on voltage-gated ion channels (Blakemore and Trombley, 2017 ), and is linked to BDNF signaling via metalloproteinase activation, which plays an important role in Trk receptor activation (Hwang et al, 2005 ).…”

Zinc modulates synaptic transmission by differentially regulating synaptic glutamate homeostasis in hippocampus

“…The presynaptic vesicular Zn 2+ is enriched through a specific Zn 2+ transporter ZnT3, and co-released with glutamate during exocytosis evoked by action potentials (AP; Ketterman & Li, 2008;Li, Hough, Suh, Sarvey, & Frederickson, 2001;Palmiter, Cole, Quaife, & Findley, 1996;Qian & Noebels, 2005;Wenzel, Cole, Born, Schwartzkroin, & Palmiter, 1997), which could directly affect synaptic transmission by interacting with receptors and channels in a glutamatergic synapse. Indeed, the application of Zn 2+ exhibits modulatory effects on a variety of membrane receptors, ion channels and transporters (Blakemore & Trombley, 2017;Frederickson, Koh, & Bush, 2005;McAllister & Dyck, 2017;Neely, Lippi, Lanzirotti, & Flinn, 2019;Sensi, Paoletti, Bush, & Sekler, 2009). Additionally, studies show that Zn 2+ can permeate both presynaptic and postsynaptic cytosols, through voltage-sensitive Ca 2+ channels (Gyulkhandanyan, Lee, Bikopoulos, Dai, & Wheeler, 2006;Kerchner, Canzoniero, Yu, Ling, & Choi, 2000;Weiss & Sensi, 2000) or Zn 2+ transporters (Colvin, 1998;Eide, 2006;McMahon & Cousins, 1998;Palmiter et al, 1996).…”