Abstract
The monoamine model of depression has long formed the basis of drug development but fails to explain treatment resistance or associations with stress or inflammation. Recent animal research, clinical trials of ketamine (a glutamate receptor antagonist), neuroimaging research, and microbiome studies provide increasing evidence of glutamatergic dysfunction in depression and other disorders. Glutamatergic involvement across diverse neuropathologies including psychoses, neurodevelopmental, neurodegenerative conditions, and brain injury forms the rationale for this review. Glutamate is the brain’s principal excitatory neurotransmitter (NT), a metabolic and synthesis substrate, and an immune mediator. These overlapping roles and multiple glutamate NT receptor types complicate research into glutamate neurotransmission. The glutamate microcircuit comprises excitatory glutamatergic neurons, astrocytes controlling synaptic space levels, through glutamate reuptake, and inhibitory GABA interneurons. Astroglia generate and respond to inflammatory mediators. Glutamatergic microcircuits also act at the brain/body interface via the microbiome, kynurenine pathway, and hypothalamus–pituitary–adrenal axis. Disruption of excitatory/inhibitory homeostasis causing neuro-excitotoxicity, with neuronal impairment, causes depression and cognition symptoms via limbic and prefrontal regions, respectively. Persistent dysfunction reduces neuronal plasticity and growth causing neuronal death and tissue atrophy in neurodegenerative diseases. A conceptual overview of brain glutamatergic activity and peripheral interfacing is presented, including the common mechanisms that diverse diseases share when glutamate homeostasis is disrupted.
Highlights
Mental disorders are one of the main causes of disability worldwide
This review describes the current understanding of the mechanisms and functions of glutamatergic neurotransmission and metabolism, in health and disease
This review has described how glutamatergic excitotoxicity in primary and stressrelated depression is seen to progress to neuronal atrophy, causing cognition and memory deficits
Summary
Mental disorders are one of the main causes of disability worldwide. In a pre-COVID pandemic WHO report of mental illness, 264 million people are affected by depression, 45 million by bipolar disorder, 20 million by schizophrenia, and 50 million by dementia [1]. Glutamate is the most-abundant amino acid in the brain and was previously considered a fuel and synthesis substrate and immune mediator [6] It was not until the 1980s that preclinical evidence emerged of glutamate as the main excitatory neurotransmitter in the central nervous system (CNS) with important roles in synaptic plasticity, learning, cognition, and memory [7,8,9,10]. Glutamine has biosynthetic roles providing carbon and nitrogen for nucleotide synthesis (purines, pyrimidines, and amino sugars), nicotinamide adenine dinucleotide phosphate (NADPH), antioxidants, and many other biosynthetic pathways involved in the maintenance of cellular integrity and function [20] Cells such as lymphocytes, neutrophils, and macrophages use glutamine as a fuel substrate under conditions of catabolic stress such as sepsis, recovery from burns or surgery, and malnutrition. The mechanism of the anti-inflammatory effects of glutamine is not well described; it has been suggested that regulation can be mediated by the balance of T-helper cell types 1 and 2 in the expression of pro-inflammatory and anti-inflammatory cytokines [23,24]
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