Role of astroglial glutamate transport on cerebral glucose metabolism in vivo : a pharmacological challenge with clozapine ; O papel do transporte glutamatérgico astrocitário no metabolismo de glicose cerebral in vivo : um desafio farmacológico com clozapina

After many decades being considered only as neuronal supporters, astrocytes are now fully integrated in the modern neuroscience as very resourceful and valuable brain cells. In this context, the contribution of astrocytes on many brain functions has become an important subject of discussion. In this regard, a topic that still remains under debate is the astrocytic participation on glucose brain metabolism and, consequently, on the uptake of the glucose analogous molecule 2-Deoxy-2-[18F]Fluoroglucose ([18F]FDG), detected by the positron emission tomography (PET). [18F]FDG-PET imaging does not offer cellular resolution, although, the resulting image reflects cellular and sub-cellular interactions with the radiopharmaceutical molecule. Until recently, the brain [18F]FDG uptake was interpreted mostly as a direct result of neuronal activity, with other cells being only seen as bystanders. However, recent studies have shown important associations between astrocyte function and [18F]FDG-PET signal, suggesting a contribution, at least partially, of these cells. Aiming to evaluate if a decline on an astrocytic function would impact on [18F]FDG-PET signal, we performed, in adult rodents, a pharmacological challenge with clozapine. This drug is known to decrease, on astrocytes, glutamate transport and the glutamate transporter 1 (GLT-1) levels. This target was chosen because strong evidence points to the activity of GLT-1 as an important trigger for glucose uptake in astrocytes. Our work focused on the region where GLT-1 is most abundant: cortex. A six-week treatment with clozapine caused, in adult rats, cortical: [18F]FDG hypometabolism, reduced GLT-1 density and expression. Alongside, was found a decline on glutamate transport, indexed by D-aspartate uptake, in cortical slices. A similar outcome was observed in cortical astrocyte primary cultures: a decrease in GLT-1 levels along with reduced D-aspartate and 2-Deoxyglucose uptake. This work provides evidence that clozapine reduces [18F]FDG-microPET signal. Our results ...