Dysfunction of homeostatic control of dopamine by astrocytes in the developing prefrontal cortex leads to cognitive impairments

Francesco Petrelli, Glenn Dallérac, Luca Pucci, Corrado Cali, Tamara Zehnder, Sébastien Sultan, Salvatore Lecca, Andrea Chicca, Andrei Ivanov, Cédric S. Asensio, Vidar Gundersen, Nicolas Toni, Graham William Knott, Fulvio Magara, Jürg Gertsch, Frank Kirchhoff, Nicole Déglon, Bruno Giros, Robert H. Edwards, Jean-Pierre MothetPaola Bezzi

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43 Scopus citations


Astrocytes orchestrate neural development by powerfully coordinating synapse formation and function and, as such, may be critically involved in the pathogenesis of neurodevelopmental abnormalities and cognitive deficits commonly observed in psychiatric disorders. Here, we report the identification of a subset of cortical astrocytes that are competent for regulating dopamine (DA) homeostasis during postnatal development of the prefrontal cortex (PFC), allowing for optimal DA-mediated maturation of excitatory circuits. Such control of DA homeostasis occurs through the coordinated activity of astroglial vesicular monoamine transporter 2 (VMAT2) together with organic cation transporter 3 and monoamine oxidase type B, two key proteins for DA uptake and metabolism. Conditional deletion of VMAT2 in astrocytes postnatally produces loss of PFC DA homeostasis, leading to defective synaptic transmission and plasticity as well as impaired executive functions. Our findings show a novel role for PFC astrocytes in the DA modulation of cognitive performances with relevance to psychiatric disorders.
Original languageEnglish (US)
JournalMolecular Psychiatry
StatePublished - Aug 20 2018

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: We would like to thank G. Carmignoto and C. Lüscher for their discussions and comments on the manuscript; K. Tan and M. Mameli for the in vivo electrophysiology of aVMAT2cKO mice; M. Rey and V. Zimmer for producing the lentivirus and performing the stereotactic surgery; C. Bellone and S. Bariselli for providing virus and advices for optogenetic experiments; the Division of Pharmacology and Toxicology and E. Grouzmann for quantifying brain monoamines; P. Fossier for sharing his electrophysiological equipment; J. Marchaland for her technical support; and J. Gremion for his help with the immunohistochemistry experiments. The study was supported by grants from the Swiss National Foundation NCCR 'Synapsy' (51NF40-158776) and 'Transcure' (51NF40-160620) to PB, operating grants from the Agence National de la Recherche (ANR-09-MNPS-022-01), Fondation pour la Recherche Médicale (Equipe FRM DEQ20150331734), CNRS, Université Aix-Marseille and Conseil Régional Provence Alpes Côte d'Azur to JPM, and NSERC RGPIN grant 385732-2012 to B.G.


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