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. 2022 Jun;49(7):2251-2264.
doi: 10.1007/s00259-022-05682-3. Epub 2022 Feb 5.

Clozapine induces astrocyte-dependent FDG-PET hypometabolism

Andréia Rocha  1 , Bruna Bellaver  1 , Débora G Souza  1 , Guilherme Schu  1   2 , Igor C Fontana  1 , Gianina T Venturin  3 , Samuel Greggio  3 , Fernanda U Fontella  1 , Manoela L Schiavenin  1 , Luiza S Machado  1 , Diogo Miron  4 , Jaderson C da Costa  3 , Pedro Rosa-Neto  5   6 , Diogo O Souza  1   7 , Luc Pellerin  8 , Eduardo R Zimmer  9   10   11
Affiliations

Clozapine induces astrocyte-dependent FDG-PET hypometabolism

Andréia Rocha et al. Eur J Nucl Med Mol Imaging. 2022 Jun.

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.

Keywords: Astrocytes; Clozapine; FDG-PET; GLT-1; Glucose; Glutamate.

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