A Neurotoxic Ménage-à-trois: Glutamate, Calcium, and Zinc in the Excitotoxic Cascade.

Alberto Granzotto,Lorella M T Canzoniero,Stefano L Sensi

doi:10.3389/fnmol.2020.600089

Abstract

Fifty years ago, the seminal work by John Olney provided the first evidence of the neurotoxic properties of the excitatory neurotransmitter glutamate. A process hereafter termed excitotoxicity. Since then, glutamate-driven neuronal death has been linked to several acute and chronic neurological conditions, like stroke, traumatic brain injury, Alzheimer’s, Parkinson’s, and Huntington’s diseases, and Amyotrophic Lateral Sclerosis. Mechanisms linked to the overactivation of glutamatergic receptors involve an aberrant cation influx, which produces the failure of the ionic neuronal milieu. In this context, zinc, the second most abundant metal ion in the brain, is a key but still somehow underappreciated player of the excitotoxic cascade. Zinc is an essential element for neuronal functioning, but when dysregulated acts as a potent neurotoxin. In this review, we discuss the ionic changes and downstream effects involved in the glutamate-driven neuronal loss, with a focus on the role exerted by zinc. Finally, we summarize our work on the fascinating distinct properties of NADPH-diaphorase neurons. This neuronal subpopulation is spared from excitotoxic insults and represents a powerful tool to understand mechanisms of resilience against excitotoxic processes.

Highlights

Excitotoxicity is a form of neuronal death triggered by excessive and/or sustained exposure to the amino acid glutamate, the primary excitatory neurotransmitter in the brain
We provide a brief overview of the role of Zn2+ in the brain and discuss its neurotoxic properties and how they intertwine with the excitotoxic cascade
Employing an array of single-cell imaging and biochemical approaches, we have demonstrated that neuronal isoform of the nitric oxide synthase (nNOS) (+) neurons fail to generate reactive oxygen species (ROS) in response to excitotoxic stimuli (Canzoniero et al, 2013; Granzotto and Sensi, 2015), a critical step that contributes to their resilience and enhanced survival upon glutamate-driven neurodegeneration

Summary

A Neurotoxic Ménage-à-trois

Mechanisms linked to the overactivation of glutamatergic receptors involve an aberrant cation influx, which produces the failure of the ionic neuronal milieu. In this context, zinc, the second most abundant metal ion in the brain, is a key but still somehow underappreciated player of the excitotoxic cascade. We discuss the ionic changes and downstream effects involved in the glutamate-driven neuronal loss, with a focus on the role exerted by zinc. We summarize our work on the fascinating distinct properties of NADPH-diaphorase neurons. This neuronal subpopulation is spared from excitotoxic insults and represents a powerful tool to understand mechanisms of resilience against excitotoxic processes

INTRODUCTION

CONCLUSION