GLT-1 Density Impacts on [18F]FDG-PET Signal

INTRODUCTION: The positron emission tomography (PET) radiopharmaceutical [18F]fluorodeoxyglucose ([18F]FDG) allows for the determination of tissue glucose consumption rate with topographical information. This technique has become one of the most important tools in the investigation of the encephalon, with applications in both research and diagnosis of various neuropsychiatric disorders. Since its inception 40 years ago, [18F]FDG PET signal is interpreted as a direct product of neuronal activity. However, neurons are not the only metabolic active cells in the brain. This neurocentric view neglects the contribution of glial cells, although some strong evidence points to an important contribution of astrocytes in the cerebral glucose metabolism. OBJECTIVES: Based on that, we hypothesize that astrocytes contribute significantly to [18F]FDG PET signal. For testing this hypothesis, we conducted a longitudinal microPET [18F]FDG in rats before and after downregulating GLT-1, the main trigger for glucose uptake in astrocytes. MATERIALS AND METHODS: Adult male Wistar rats received clozapine in the drinking water for six weeks as a strategy for reducing GLT-1. In vivo glucose brain metabolism was longitudinally accessed using [18F]FDG microPET before and after the treatment. Cortical immunocontent and expression of glutamate transporters GLT-1 and GLAST were assessed. Moreover, the cortex was also used for preparing an adult astrocytic culture, which was analyzed for [3H]D-Aspartate and [3H]2-Deoxyglucose uptake. DISCUSSION AND RESULTS: The clozapine treatment significantly reduced [18F]FDG metabolism, with local maxima in the cortex. The immunocontent and expression of the glutamate transporter GLT-1 were also significantly reduced in the same region. A similar trend was seen in the cortical adult primary astrocytic culture, with a reduction tendency of GLT-1 density, D-aspartate uptake and 2-Deoxyglucose uptake. CONCLUSION: This work provides evidence suggesting that astrocytic glutamate transporter GLT-1 down-regulation reduces [18F]FDG PET signal in cortical layers. These early results indicates that astrocytes may contribute to [18F]FDG PET interpretation.