The glutamate-glutamine cycle is closely linked to cellular energy metabolism. Glutamate and glutamine are extensively recycled between neurons and astrocytes in a process known as the glutamate-glutamine cycle. Glucose is the primary substrate for the synthesis of glutamate. Furthermore, glutamate synthesis and metabolism is closely connected to both neuronal and astrocytic energy metabolism through the TCA cycle. Astrocytes express the major anaplerotic enzyme in the brain pyruvate carboxylase (PC) catalyzing the conversion of pyruvate to oxaloacetate which is essential for de novo glutamate synthesis. This pathway is absent in neurons and pyruvate must enter the TCA cycle via pyruvate dehydrogenase (PDH). Glutamate is released to the synaptic cleft from vesicles in the presynaptic neurons, hereby mediating excitatory signals in the postsynaptic neuron. Glutamate is primarily removed from the synapse by astrocytic uptake via the transporters GLT-1 and GLAST. However, a fraction is also removed by neuronal uptake primarily mediated by GLT-1 activity. In the astrocyte, glutamate is converted into glutamine by the enzyme glutamine synthetase (GS) which is only found in astrocytes. Glutamine may be released from astrocytes through SNAT3/5 and is taken up by neurons primarily by SNAT1/7/8. Once taken up into the neurons, glutamine is converted by phosphate-activated glutaminase (PAG) into glutamate and the cycle is thereby completed. Note that SNAT1/7/8 are localized in the axon terminal for diagrammatic purposes to indicate expression in neurons. The SNATs expressed specifically in axon terminals have not been definitively identified (Conti and Melone, 2006; Erickson, 2017). Glutamate is also oxidatively metabolized in the TCA cycle in both neurons and astrocytes, primarily via the enzymes aspartate aminotransferase (AAT) and glutamate dehydrogenase (GDH).

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... (MAS, see Fig. 3). Glutamate can also undergo oxidative deamination to α-ketoglutarate via the enzyme glutamate dehydrogenase (GDH), which serves as an anaplerotic pathway in both neurons and astrocytes. Finally, glutamate and glutamine are extensively recycled between neurons and astrocytes in a process called the glutamateglutamine cycle (see Fig. 2). In astrocytes, glutamate is converted into glutamine by fixation of NH 4 + via the enzyme glutamine synthetase (GS), an enzyme exclusively expressed in astrocytes. Conversely, glutamine is converted back into glutamate with the release of NH 4 + by the enzyme phosphate-activated glutamine (PAG), which is predominantly located in ...

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... glutamate participates in a highly active recycling process between presynaptic glutamatergic neurons and astrocytes, known as the glutamate-glutamine cycle ( Fig. 2) (Bak et al., 2006;Hertz, 2013;Hertz and Rothman, 2016). Astrocytes are closely associated with the glutamatergic synapse and are responsible for the majority of extracellular glutamate uptake, whereas a minor fraction is recovered by neuronal uptake (Hertz and Schousboe, 1987;Lehre and Danbolt, 1998;Zhou and Danbolt, 2013). Although ...

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... in astrocytes. De novo glutamate synthesis is dependent on sufficient anaplerosis, i.e. reactions providing a net increase in TCA cycle intermediates (Sonne- wald, 2014). The primary anaplerotic enzyme in the brain, pyruvate carboxylase (PC), is exclusively expressed in astrocytes and serves as the main pathway of de novo glutamate synthesis (Fig. 2) ( Schousboe et al., 2019;Yu et al., 1983;¨ Oz et al., 2004). The selective expression of PC in astrocytes, in combination with the essential role of astrocyte-derived glutamine, underlines the fact that neuronal glutamate homeostasis is under tight astrocytic control ( Schousboe et al., ...

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... leucine, isoleucine and valine are readily transported across the blood brain barrier and are important nitrogen donors for glutamate synthesis via BCAT activity (Sperringer et al., 2017;Yudkoff, 1997) which is crucial for de novo synthesis of glutamate ( Conway and Hutson, 2016). Since there is a net flow of glutamate from neurons to astrocytes (Fig. 2), the cell-specific metabolism of glutamate is an area of great interest as discussed in detail ...

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... of both the cytosolic and mitochondrial isoforms of AAT has been reported in both human AD brain samples and animal models ( Li et al., 2020;Mahajan et al., 2020;Puthiyedth et al., 2016;Savas et al., 2017). Lower activity or expression of AAT could disturb glutamate synthesis and metabolism, but could also have significant impact on MAS activity (Fig. 3) (McKenna et al., 2006), which in turn may contribute to the cerebral bioenergetic crisis of AD. Intriguingly, we recently found a selective reduction in astrocytic aspartate synthesis in hippocampal slices of 5xFAD mice (Andersen et al., 2021), which may indicate that astrocyte-specific metabolic deficiencies in AD disrupt aspartate and glutamate ...

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... et al., 2014;Carter, 1982;Hosp et al., 2017;Liévens et al., 2001;Tong et al., 2014). We have also recently reported reduced cerebral GS expression is the R6/2 mice ( Skotte et al., 2018). Interestingly, we also found decreased expression of the glutamine transporter SNAT3 ( Skotte et al., 2018), which is primarily expressed in astrocytes (Fig. 2). This could lead to a reduced capacity of astrocyte glutamine release, which may explain the reported accumulation of cerebral glutamine in HD. In the same study we also investigated functional metabolism in cerebral cortical and striatal slices of R6/2 mice. Surprisingly, we observed that glucose metabolism was largely maintained in ...