Studies of the last two decades have demonstrated the presence in astrocytic cell membranes of N-methyl-d-aspartate (NMDA) receptors (NMDARs), albeit their apparently low abundance makes demonstration of their presence and function more difficult than of other glutamate (Glu) receptor classes residing in astrocytes. Activation of astrocytic NMDARs directly in brain slices and in acutely isolated or cultured astrocytes evokes intracellular calcium increase, by mutually unexclusive ionotropic and metabotropic mechanisms. However, other than one report on the contribution of astrocyte-located NMDARs to astrocyte-dependent modulation of presynaptic strength in the hippocampus, there is no sound evidence for the significant role of astrocytic NMDARs in astrocytic-neuronal interaction in neurotransmission, as yet. Durable exposure of astrocytic and neuronal co-cultures to NMDA has been reported to upregulate astrocytic synthesis of glutathione, and in this way to increase the antioxidative capacity of neurons. On the other hand, overexposure to NMDA decreases, by an as yet unknown mechanism, the ability of cultured astrocytes to express glutamine synthetase (GS), aquaporin-4 (AQP4), and the inward rectifying potassium channel Kir4.1, the three astroglia-specific proteins critical for homeostatic function of astrocytes. The beneficial or detrimental effects of astrocytic NMDAR stimulation revealed in the in vitro studies remain to be proven in the in vivo setting.

The most common malignant brain tumors are those of astrocytic origin, gliomas, with the most aggressive glioblastoma (WHO grade IV) among them. Despite efforts, medicine has not made progress in terms of the prognosis and life expectancy of glioma patients. Behind the malignant phenotype of gliomas lies multiple genetic mutations leading to reprogramming of their metabolism, which gives those highly proliferating cells an advantage over healthy ones. The so-called glutamine addiction is a metabolic adaptation that supplements oxidative glycolysis in order to secure neoplastic cells with nutrients and energy in unfavorable conditions of hypoxia. The present review aims at presenting the research and clinical attempts targeting the different metabolic pathways involved in glutamine metabolism in gliomas. A brief description of the biochemistry of glutamine transport, synthesis, and glutaminolysis, etc. will forego a detailed comparison of the therapeutic strategies undertaken to inhibit glutamine utilization by gliomas.

Background: Excessive accumulation of ammonia in the brain is a causative factor of an array of neurological manifestations of hyperammonemic encephalopathies (“hyperammonemias”, HA) among which hepatic encephalopathy (HE) is a major epidemiologic and therapeutic challenge. While ammonia neurotoxicity is symptomatically and mechanistically very complex, there is a consensus with regard to the leading role in its pathogenesis of: i) astrocytes being the primary cellular target of ammonia toxicity; ii) alterations of glutamate (Glu)-dependent neurotransmission (over-excitation followed by inhibition of glutamatergic tone) being the cornerstone of its neurophysiological manifestations; and iii) brain edema, an often lethal consequence of astrocytic swelling, being among other factors caused by the retention of glutamine (Gln) in these cells. Objective: This article critically evaluates the present literature attempting to relate manifestations of HA to changes in astrocytic Glu and Gln transport as observed in different in vivo and in vitro HA and/or HE models. Emphasis is put on two disproportions in the state of the art: i) the paucity of available data regarding ammonia-dependent changes in Glu transport activity vs the relative abundance of information on the expression of astrocytic Glu transporters (GLT-1/EAAT2 and GLAST/EAAT1); ii) the just emerging still not very conclusive knowledge on the response of astrocytic Gln transporters SN1 and SN2. Conclusion: The review on the above issues is complemented by own recent data which fill some of the many gaps in the knowledge. A brief account is included on the roles of heteromeric cell membrane Glu/arginine (Arg) exchanger y+LAT2 and on the mitochondrial Gln transport.