Glucose is the primary energy source for mammalian brain and its delivery is mediated by a family of glucose transporter proteins (GLUTs). However, under certain circumstances such as suckling, starvation, and diabetes, monocarboxcyclic acids, i.e. ketone bodies, lactate, and pyruvate can serve as alternative fuels for cerebral metabolism. The uptake of these substrates are mediated by proton-coupled monocarboxcyclic acid transporters (MCTs). In collaboration with Drs W and K Landshulz, we have cloned two MCTs (MCT 1 and MCT 2) from a mouse kidney cDNA library and characterized their cerebral localization by in situ hybridization. MCT1 is widely expressed in the adult mouse brain. It is found highly expressed in neurons of the cortex, hippocampus, and cerebellum as well as in microvessels of the blood-brain barrier, ependymal lining of the cerebral ventricles, choroid plexus and white matter tract of the corpus callosum. MCT2 expression appears to be restricted to neurons with the highest expression observed in the granule cells of the dentate gyrus and Purkinjie and granule cells of the cerebellum. During development in the rat there appears to be a coordinate regulation of MCT and GLUT expression coincident with substrate availability. Peak levels of circulating ketone bodies and maximal B hydroxybutarate utilization are observed at postnatal days 10-17 (P10-P17). MCT 1 is widely expressed in the newborn brain with high levels of expression observed in microvessels and neurons of the hippocampus and thalamus. Maximum expression is observed at P-14 and declines at P21, upon weaning, to adult levels. MCT 2 expression remains restricted and slowly increases with development. Similarly GLUT1 expression remains fairly constant through P1-P14 and then progressively increases through to adulthood. In contrast GLUT3 expression while low through P-14 dramatically increases through P21 and declines slightly through to adulthood consistent with peak glucose utilization. We are currently investigating whether similar coordinate regulation exists in paradigms of starvation and diabetes. In related studies we have begun to investigate the role of the MCTs and GLUTs in astrocytic and neuronal survival following an ischemic injury in control and diabetic rats. Studies of middle cerebral artery occlusion (MCAO) in the spontaneous hypertensive (SH) rat have revealed a rapid loss of GLUT1 and MCT1 expression in the core of the infarct while the loss of MCT2 and GLUT3 occurs more slowly. Conversely there is a rapid and dramatic increase in MCTI and GLUT1 expression in the peri-infarct and adjacent ipsalateral hemisphere in activated astrocytes which are believed to support tissue recovery, neuronal survival and scar formation.
