KAUST Research Workshop on Innovative Technologies to Study Brain Energy Metabolism
University College London, UK
Alexander Guorine is Professor at the Centre for Cardiovascular and Metabolic Neuroscience, University College London.
Astrocytes support neuronal function by providing essential structural and nutritional support, neurotransmitter trafficking and recycling and may also contribute to brain information processing. Our recent data obtained using in vivo 2P imaging and real-time biosensor recording of glial signalling molecules and metabolic substrates suggest that astrocytes also function as versatile metabolic sensors of CNS milieu and play an important role in the maintenance of brain metabolic homeostasis. Anatomical and functional features of astrocytes allow them to detect and respond to changes in the brain parenchymal levels of metabolic substrates (oxygen), and metabolic waste products (carbon dioxide). The hypoxia sensor of astrocytes resides in the mitochondria where oxygen is consumed. Physiological decreases in PO2 inhibit astroglial mitochondrial respiration, leading to production of free radicals, lipid peroxidation, activation of phospholipase C, IP3 receptors and recruitment of Ca2+ from the intracellular stores. In pH-sensitive astrocytes, CO2-induced acidification activates Na+/HCO3- cotransporter NBCe1 which brings Na+ inside the cell. Raising [Na+]i activates Na+/Ca2+ exchanger (NCX) to operate in a reverse mode leading to Ca2+ entry. Hypoxia- or low pH-induced [Ca2+]i increases in astrocytes lead to vesicular fusion and release of ATP. ATP mediates communication between astrocytes and neighbouring neurons and at the level of the lower brainstem modulates the activities of the respiratory and autonomic neuronal networks that ensure adaptive changes in breathing and sympathetic drive in order to support the physiological and behavioural demands of the organism in ever-changing environmental conditions. Together recent experimental data suggest that astrocytes are functionally specialized CNS metabolic sensors tuned for rapid detection of physiological changes in brain PO2, PCO2, and pH. (Supported by The Wellcome Trust and the British Heart Foundation).