Milestone Review: Metabolic dynamics of glutamate and GABA mediated neurotransmission — The essential roles of astrocytes

Abstract

Since it was first generally accepted that the two amino acids glutamate and GABA act as principal neurotransmitters, several landmark discoveries relating to this function have been uncovered. Synaptic homeostasis of these two transmitters involves several cell types working in close collaboration and is facilitated by specialized cellular processes. Notably, glutamate and GABA are extensively recycled between neurons and astrocytes in a process known as the glutamate/GABA-glutamine cycle, which is essential to maintain synaptic transmission. The glutamate/GABAglutamine cycle is intimately coupled to cellular energy metabolism and relies on the metabolic function of both neurons and astrocytes. Importantly, astrocytes display unique metabolic features allowing extensive metabolite release, hereby providing metabolic support for neurons. Furthermore, astrocytes undergo complex metabolic adaptations in response to injury and pathology, which may greatly affect the glutamate/GABA-glutamine cycle and synaptic transmission during disease. In this Milestone Review we outline major discoveries in relation to synaptic balancing of glutamate and GABA signaling, including cellular uptake, metabolism, and recycling.We provide a special focus on how astrocyte function and metabolism contribute to sustain neuronal transmission through metabolite transfer. Recent advances on cellular glutamate and GABA homeostasis are reviewed in the context of brain pathology, including glutamate toxicity and neurodegeneration. Finally, we consider how pathological astrocyte metabolism may serve as a potential target of metabolic intervention. Integrating the multitude of fine-tuned cellular processes supporting neurotransmitter recycling, will aid the next generation of major discoveries on brain glutamate and GABA homeostasis.

Astrocytic GABAergic Regulation in Alcohol Use and Major Depressive Disorders

“…GAT3 activities influence various astrocytic functions encompassing the regulation of inhibitory synapse efficacy, excitatory neurotransmission, and astrocyte synaptic proximity, underscoring the role of GAT3 as a key glial GABA transporter [65,66]. Interestingly, the genetic ablation of GAT3 is lethal in mice, suggesting its critical role in GABA homeostasis during early embryogenesis and development [67].…”

“…The GABA taken up by astrocytes via GABA transporters is either recycled into the GABA/glutamine cycle, which plays critical roles in GABA metabolism between neurons and astrocytes (Figure 2), or metabolized within mitochondria by the GABA transaminase (GABA-T) enzyme, which is present in both neurons and astrocytes [53,70]. Importantly, research has demonstrated that almost half of the released GABA is taken up and metabolized by astrocytes, underscoring their role in regulating GABA levels in the CNS [67]. Therefore, it is evident that astrocytes are considered essential cells in maintaining GABA homeostasis in the brain.…”

“…GAT3 activities influence various astrocytic functions encompassing the regulation of inhibitory synapse efficacy, excitatory neurotransmission, and astrocyte synaptic proximity, underscoring the role of GAT3 as a key glial GABA transporter [65,66]. Interestingly, the genetic ablation of GAT3 is lethal in mice, suggesting its critical role in GABA homeostasis during early embryogenesis and development [67]. Furthermore, astrocytic GABA release is facilitated by permeable membrane channels, such as BEST1, which is a calcium-dependent anion channel and is considered a vital mechanism of astrocytic GABA release [51].…”

Recent advances in the biosynthesis and industrial biotechnology of Gamma-amino butyric acid

“…This synthesis pathway, mediated by the enzyme (GAD), results in the production of GABA, which plays a crucial role in regulating neuronal excitability and the overall stability of the neural network. Furthermore, glutaminase and glutamine synthetase play crucial functions in glutamic acid, glutamine, and ammonia homeostasis in the brain, which is intimately connected to GABA biosynthesis (Andersen and Schousboe 2023 ).…”

Elucidating the Biochemical Role of Novel Enzyme Targets in Neurodegenerative Disorders

“…Historically, our understanding of these disorders was limited. However, with advancements in neuroscience and molecular biology, we have started to unravel the intricacies of their onset and progression [4]. Common neurodegenerative disorders include Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), among others.…”