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Cited by 31Neuroscience and Neuropharmacology ResearchAmino Acid Enzymes and MetabolismAdvanced MRI Techniques and Applications

Clozapine induces astrocyte-dependent FDG-PET hypometabolism

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Rocha, Andréia, Bellaver, Bruna, Souza, Débora G., Schu, Guilherme, Fontana, Igor C., Venturin, Gianina T., Greggio, Samuel, Fontella, Fernanda U. +8 more·2022·European Journal of Nuclear Medicine and Molecular Imaging
DOI 10.1007/s00259-022-05682-3

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Abstract

Purpose Advances in functional imaging allowed us to visualize brain glucose metabolism in vivo and non-invasively with [18 F]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.

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  • Astrocyte hypometabolism is associated with neuronal dysfunction, age, and disease.

    “Astrocyte hypometabolism has been described to be associated with neuronal dysfunction, age, and disease [68,69].”

    From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [68]

    The Introduction (page unavailable) links reduced astrocytic glutamate uptake to reduced glucose uptake and discusses whether this could produce FDG-PET hypometabolism like that seen in neurodegenerative disorders. The Discussion (page unavailable) says the authors reproduced a hypometabolic pattern seen in dementia by reducing astrocytic glutamate transport. These passages support a connection to disease-related hypometabolism, but they do not establish an association of astrocyte hypometabolism with age or neuronal dysfunction. (LLM, conf=0.83)

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Authors
Rocha, A., Bellaver, B., Souza, D. G., Schu, G., Fontana, I. C., Venturin, G. T., Greggio, S., Fontella, F. U., Schiavenin, M. L., Machado, L. S., Miron, D., da Costa, J. C., Rosa-Neto, P., Souza, D. O., Pellerin, L., & Zimmer, E. R.
Affiliations
  • Universidade Federal do Rio Grande do Sul (BR)
  • Instituto do Cérebro (BR)
  • Inserm (FR)
Corresponding author
Zimmer, Eduardo R.
ORCID
Venue
European Journal of Nuclear Medicine and Molecular Imaging
Publisher
Springer Science and Business Media LLC
Published
2022-02-05
Volume
49
Issue
7
Pages
2251-2264
ISSN
  • 1619-7070 (ISSN-L)
  • 1619-7089
DOI
10.1007/s00259-022-05682-3
OpenAlex
W4225867126
Cited by
31
References
3
Citations by year
2026: 3 · 2025: 5 · 2024: 8 · 2023: 9 · 2022: 6
FWCI
3.10
Type
journal article
Language
en
Open access
Licence
Locations
  • European Journal of Nuclear Medicine and Molecular Imaging (publishedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • Lume (Universidade Federal do Rio Grande do Sul) (submittedVersion, cc-by-nc-sa)
Funders
  • Institut National de la Santé et de la Recherche Médicale
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (2014-4, 88887, 88887.336490/2019‐00, /2019‐00, 2020-00, 88887.185806/2018-00, 465671/2014-4)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (435642/2018- 9, 465671/2014‐4, 312410/2018‐2, /2019-0, 152189/2020-3, 440763/2016‐9, 2014-4, 2020-00, 16/2551‐0000475‐7)
  • Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (465671/2014-4, 19/2551, 16/2551–0000475–7, 2014-4, 16/2551, 19/2551-0000700-0)
  • Instituto Serrapilheira (/2018, Serra‐1912‐31365)
  • Université de Poitiers
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
Keywords
clozapine, FDG-PET hypometabolism, astrocytes, GLT-1, astrocyte-neuron lactate shuttle, brain glucose metabolism, GLAST, glutamate uptake, antipsychotic drugs, dementia
MeSH terms
Animals, Astrocytes, Clozapine, Glucose, Humans, Male, Rats, Wistar, Glutamic Acid, Fluorodeoxyglucose F18, Positron-Emission Tomography, Rats

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