Overview of Glutamatergic Dysregulation in Central Pathologies

Abstract

As the major excitatory neurotransmitter in the mammalian central nervous system, glutamate plays a key role in many central pathologies, including gliomas, psychiatric, neurodevelopmental, and neurodegenerative disorders. Post-mortem and serological studies have implicated glutamatergic dysregulation in these pathologies, and pharmacological modulation of glutamate receptors and transporters has provided further validation for the involvement of glutamate. Furthermore, efforts from genetic, in vitro, and animal studies are actively elucidating the specific glutamatergic mechanisms that contribute to the aetiology of central pathologies. However, details regarding specific mechanisms remain sparse and progress in effectively modulating glutamate to alleviate symptoms or inhibit disease states has been relatively slow. In this report, we review what is currently known about glutamate signalling in central pathologies. We also discuss glutamate's mediating role in comorbidities, specifically cancer-induced bone pain and depression.

Keywords: excitotoxicity; glutamate; glutamate dysregulation; neurodegenerative disease; psychiatric disorder.

Figure 1

Schematic illustration of the relationship between glutamate dysregulation and central pathologies. Psychiatric disorders, including depression and various anxiety disorders, induce differential glutamate transmission across the brain, particularly in the prefrontal cortex (PFC), anterior cingulate cortex (ACC), and hippocampus. In acute and chronic neurodegenerative conditions, glutamate transport dysregulation is largely attributable to glutamate transporter protein downregulation. The use of pharmacological reagents to strategically manipulate glutamate transmission can elucidate the specific molecular influences of glutamate dysregulation on central pathologies.