Glutamate and ATP at the Interface of Metabolism and Signaling in the Brain

Christina L Ruby, Katheryn M O'Connor, Jennifer Ayers-Ringler, Doo-Sup Choi, Christina L. Ruby, Katheryn M. O’Connor, Ruby, Christina L., O’Connor, Katheryn M., Ayers-Ringler, Jennifer, Choi, Doo-Sup

Recent studies have demonstrated that the function of glia is not restricted to the support of neuronal function. In fact, astrocytes are essential for neuronal activity in the brain and play an important role in the regulation of complex behavior. Astrocytes actively participate in synapse formation and brain information processing by releasing and uptaking glutamate, D-serine, adenosine 5'-triphosphate (ATP), and adenosine. In the central nervous system, adenosine-mediated neuronal activity modulates the actions of other neurotransmitter systems. Adenosinergic fine-tuning of the glutamate system in particular has been shown to regulate circadian rhythmicity and sleep, as well as alcohol-related behavior and drinking. Adenosine gates both photic (light-induced) glutamatergic and nonphotic (alerting) input to the circadian clock located in the suprachiasmatic nucleus of the hypothalamus. Astrocytic, SNARE-mediated ATP release provides the extracellular adenosine that drives homeostatic sleep. Acute ethanol increases extracellular adenosine, which mediates the ataxic and hypnotic/sedative effects of alcohol, while chronic ethanol leads to downregulated adenosine signaling that underlies insomnia, a major predictor of relapse. Studies using mice lacking the equilibrative nucleoside transporter 1 have illuminated how adenosine functions through neuroglial interactions involving glutamate uptake transporter GLT-1 [referred to as excitatory amino acid transporter 2 (EAAT2) in human] and possibly water channel aquaporin 4 to regulate ethanol sensitivity, reward-related motivational processes, and alcohol intake.