Glutamate metabolism and recycling at the excitatory synapse in health and neurodegeneration

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Glutamate is the primary excitatory neurotransmitter of the brain. Cellular homeostasis of glutamate is of paramount importance for normal brain function and relies on an intricate metabolic collaboration between neurons and astrocytes. Glutamate is extensively recycled between neurons and astrocytes in a process known as the glutamate-glutamine cycle. The recycling of glutamate is closely linked to brain energy metabolism and is essential to sustain glutamatergic neurotransmission. However, a considerable amount of glutamate is also metabolized and serves as a metabolic hub connecting glucose and amino acid metabolism in both neurons and astrocytes. Disruptions in glutamate clearance, leading to neuronal overstimulation and excitotoxicity, have been implicated in several neurodegenerative diseases. Furthermore, the link between brain energy homeostasis and glutamate metabolism is gaining attention in several neurological conditions. In this review, we provide an overview of the dynamics of synaptic glutamate homeostasis and the underlying metabolic processes with a cellular focus on neurons and astrocytes. In particular, we review the recently discovered role of neuronal glutamate uptake in synaptic glutamate homeostasis and discuss current advances in cellular glutamate metabolism in the context of Alzheimer's disease and Huntington's disease. Understanding the intricate regulation of glutamate-dependent metabolic processes at the synapse will not only increase our insight into the metabolic mechanisms of glutamate homeostasis, but may reveal new metabolic targets to ameliorate neurodegeneration.

Original languageEnglish
Article number108719
Number of pages14
Publication statusPublished - 2021

Bibliographical note

Funding Information:
The Scholarship of Peter & Emma Thomsen is gratefully acknowledged for personal financial support to JVA. PAR was supported by NIH grants NS066019 , MH104318 , EY027881 , HD018655 .

Publisher Copyright:
© 2021 The Authors

    Research areas

  • Alzheimer's disease (AD), Aspartate aminotransferase (AAT), Glutamate dehydrogenase (GDH), Glutamate-glutamine cycle, Glutamic acid, Huntington's disease (HD), Malate-aspartate shuttle (MAS), Neurotransmitter recycling

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