Role of astroglial glutamate transport on cerebral glucose metabolism in vivo : a pharmacological challenge with clozapine

• Ano de defesa: 2019
• Autor(a) principal: Rocha, Andréia Silva da
• Orientador(a): Zimmer, Eduardo Rigon
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: eng
• Palavras-chave em Português: Astrócitos; Ácido glutâmico; Clozapina; Glucose : Metabolismo; Fluordesoxiglucose F18
• Link de acesso: http://hdl.handle.net/10183/201659

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 indicate that astrocytes are, at least partially, the cells underlying the glucose brain metabolism response to clozapine. Also, it suggests the reduction on GLT-1 levels/glutamate transport in astrocytes as a mechanism by which this response could be generated. These results raise the need for a reevaluation in the way that brain research and clinical [18F]FDG-PET data are interpreted, paying particular attention to the potential contribution of cells other than just neurons. Additionally, clozapine is a drug approved for clinical use, therefore, this phenomenon should be carefully investigated in patients under its treatment.