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Glutamate-Related Biomarkers for Neuropsychiatric Disorders

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The glutamate receptor plays an important role in synaptic plasticity, learning, memory, and the pathogenesis and pathophysiology of numerous neuropsychiatric disorders such as schizophrenia, depression, post-traumatic stress disorder, addiction, autism, ADHD, autoimmune encephalitis, and neurodegenerative ...

The glutamate receptor plays an important role in synaptic plasticity, learning, memory, and the pathogenesis and pathophysiology of numerous neuropsychiatric disorders such as schizophrenia, depression, post-traumatic stress disorder, addiction, autism, ADHD, autoimmune encephalitis, and neurodegenerative diseases such as Alzheimer's disease.

For example, both ionotropic (especially NMDA and AMPA) and metabotropic (mGLU) receptors were reported to be involved in schizophrenia. In details, taking NMDA receptors as an example, the receptors are widely distributed in most major organs (including heart, ovary, kidney, gastrointestinal system, lung and etc.) and tissue types (including ganglia cells, nerve fibers, blood vessels, enteroendocrine cells, liver, mast cells, inflammatory cells and etc.). The NMDA receptor has binding sites not only for glutamate or aspartate, but also a separate coagonist site for the endogenous ligands, D-serine, D-alanine, and glycine. Occupancy of the coagonist site can increase the frequency of opening of the channels activated by NMDA agonists, facilitating excitatory transmission in the brain. In fact, the binding of both glycine (or D-serine, D-alanine) and glutamate is required to open the NMDA receptor channel ionophore. Recently, D-aspartate was found to play an important role too.

Some of the NMDA receptors isolated from peripheral tissues have been cloned and sequenced. These sequences correspond with NMDA receptors that have been cloned in the CNS. Further physiological and pharmacological experiments support the hypothesis that NMDA receptors in the periphery have similar properties to those in the CNS or expressed in host cells transfected with cloned subunits. Physiological studies with agonists and antagonists of the NMDAR 1 receptor in the pig ileum have shown that these receptors are similar to those characterized in the CNS.

Direct measurement of physiological changes and NMDA-related biomarkers in human brains is nearly impossible because of invasive testing procedures and ethical issues. Thus, developing accessible peripheral biomarkers becomes more important for mental illness. Peripheral gene expression may be a useful surrogate for gene expression in the CNS when the relevant gene is expressed in both. Lymphocytes or white cells have been suggested to be a neural probe because numerous studies showed similarities between receptor expression and mechanisms of transduction processes of cells in the nervous system (e.g. neurons and glia) and lymphocytes. Blood-derived RNA has also become a convenient alternative to traditional tissue biopsy-derived RNA. Therefore, peripheral gene expressions as well as other peripheral biomarkers might have potential to be surrogate CNS biomarkers for disorders, their outcomes, and treatment responses in the central nervous system.

To facilitate the development of glutamate-related biomarkers for neuropsychiatric disorders, the aim of this Research Topic is to gather a comprehensive body of review or original articles to update the current state of this increasingly important theme.


Keywords: Glutamate, Biomarker, Schizophrenia, Dementia, Depression


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