Andréia Rocha1, Bruna Bellaver1, Débora G Souza1, Guilherme Schu1,2, Igor C Fontana1, Gianina T Venturin3, Samuel Greggio3, Fernanda U Fontella1, Manoela L Schiavenin1, Luiza S Machado1, Diogo Miron4, Jaderson C da Costa3, Pedro Rosa-Neto5,6, Diogo O Souza1,7, Luc Pellerin8, Eduardo R Zimmer9,10,11. 1. Graduate Program in Biological Sciences: Biochemistry, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil. 2. Proaction Laboratory, Faculty of Psychology and Education Sciences, University of Coimbra, Coimbra, Portugal. 3. Preclinical Research Center, Brain Institute (BraIns) of Rio Grande Do Sul, Pontifical Catholic University of Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil. 4. Faculty of Pharmacy, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil. 5. Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Montreal, Canada. 6. Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, Canada. 7. Department of Biochemistry, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil. 8. Inserm U1313, Université et CHU de Poitiers, Poitiers, France. 9. Graduate Program in Biological Sciences: Biochemistry, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil. eduardo.zimmer@ufrgs.br. 10. Graduate Program in Biological Sciences: Pharmacology and Therapeutics, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil. eduardo.zimmer@ufrgs.br. 11. Department of Pharmacology, Universidade Federal Do Rio Grande Do Sul, (UFRGS), 2600 Ramiro Barcelos St, Porto Alegre, RS, 90035-003, Brazil. eduardo.zimmer@ufrgs.br.
Abstract
PURPOSE: Advances in functional imaging allowed us to visualize brain glucose metabolism in vivo and non-invasively with [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) imaging. In the past decades, FDG-PET has been instrumental in the understanding of brain function in health and disease. The source of the FDG-PET signal has been attributed to neuronal uptake, with hypometabolism being considered as a direct index of neuronal dysfunction or death. However, other brain cells are also metabolically active, including astrocytes. Based on the astrocyte-neuron lactate shuttle hypothesis, the activation of the glutamate transporter 1 (GLT-1) acts as a trigger for glucose uptake by astrocytes. With this in mind, we investigated glucose utilization changes after pharmacologically downregulating GLT-1 with clozapine (CLO), an anti-psychotic drug. METHODS: Adult male Wistar rats (control, n = 14; CLO, n = 12) received CLO (25/35 mg kg-1) for 6 weeks. CLO effects were evaluated in vivo with FDG-PET and cortical tissue was used to evaluate glutamate uptake and GLT-1 and GLAST levels. CLO treatment effects were also assessed in cortical astrocyte cultures (glucose and glutamate uptake, GLT-1 and GLAST levels) and in cortical neuronal cultures (glucose uptake). RESULTS: CLO markedly reduced in vivo brain glucose metabolism in several brain areas, especially in the cortex. Ex vivo analyses demonstrated decreased cortical glutamate transport along with GLT-1 mRNA and protein downregulation. In astrocyte cultures, CLO decreased GLT-1 density as well as glutamate and glucose uptake. By contrast, in cortical neuronal cultures, CLO did not affect glucose uptake. CONCLUSION: This work provides in vivo demonstration that GLT-1 downregulation induces astrocyte-dependent cortical FDG-PET hypometabolism-mimicking the hypometabolic signature seen in people developing dementia-and adds further evidence that astrocytes are key contributors of the FDG-PET signal.
PURPOSE: Advances in functional imaging allowed us to visualize brain glucose metabolism in vivo and non-invasively with [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) imaging. In the past decades, FDG-PET has been instrumental in the understanding of brain function in health and disease. The source of the FDG-PET signal has been attributed to neuronal uptake, with hypometabolism being considered as a direct index of neuronal dysfunction or death. However, other brain cells are also metabolically active, including astrocytes. Based on the astrocyte-neuron lactate shuttle hypothesis, the activation of the glutamate transporter 1 (GLT-1) acts as a trigger for glucose uptake by astrocytes. With this in mind, we investigated glucose utilization changes after pharmacologically downregulating GLT-1 with clozapine (CLO), an anti-psychotic drug. METHODS: Adult male Wistar rats (control, n = 14; CLO, n = 12) received CLO (25/35 mg kg-1) for 6 weeks. CLO effects were evaluated in vivo with FDG-PET and cortical tissue was used to evaluate glutamate uptake and GLT-1 and GLAST levels. CLO treatment effects were also assessed in cortical astrocyte cultures (glucose and glutamate uptake, GLT-1 and GLAST levels) and in cortical neuronal cultures (glucose uptake). RESULTS: CLO markedly reduced in vivo brain glucose metabolism in several brain areas, especially in the cortex. Ex vivo analyses demonstrated decreased cortical glutamate transport along with GLT-1 mRNA and protein downregulation. In astrocyte cultures, CLO decreased GLT-1 density as well as glutamate and glucose uptake. By contrast, in cortical neuronal cultures, CLO did not affect glucose uptake. CONCLUSION: This work provides in vivo demonstration that GLT-1 downregulation induces astrocyte-dependent cortical FDG-PET hypometabolism-mimicking the hypometabolic signature seen in people developing dementia-and adds further evidence that astrocytes are key contributors of the FDG-PET signal.
Authors: Patrick Jakoby; Elke Schmidt; Iván Ruminot; Robin Gutiérrez; L Felipe Barros; Joachim W Deitmer Journal: Cereb Cortex Date: 2012-10-04 Impact factor: 5.357