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

Francesco Petrelli (1) , Glenn Dallérac (2, 3) , Luca Pucci (4) , Corrado Calì (1) , Tamara Zehnder (1) , Sébastien Sultan (5) , Salvatore Lecca (6) , Andrea Chicca (7) , Andrei Ivanov (8) , Cédric Asensio (9) , Vidar Gundersen (10) , Nicolas Toni (1) , Graham William Knott (11) , Fulvio Magara (1) , Jürg Gertsch (7) , Frank Kirchhoff (12) , Nicole Déglon (13) , Bruno Giros (14) , Robert Edwards (9) , Jean-Pierre Mothet (15, 3) , Paola Bezzi (1)

1 UNIL - Université de Lausanne = University of Lausanne
2 NeuroPSI - Institut des Neurosciences Paris-Saclay
3 CRN2M - Centre de recherche en neurobiologie - neurophysiologie de Marseille
4 University of Naples Federico II = Università degli studi di Napoli Federico II
5 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
6 Institut du Fer à Moulin
7 UNIBE - Universität Bern / University of Bern
8 LPQM - Laboratoire de Photonique Quantique et Moléculaire
9 UC San Francisco - University of California [San Francisco]
10 Division of Anatomy [Oslo]
11 EPFL - Ecole Polytechnique Fédérale de Lausanne
12 Saarland University [Saarbrücken]
13 CHUV - Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
14 NPS - Neuroscience Paris Seine
15 éTICC

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.

Domaines: Sciences du Vivant [q-bio]; Neurosciences [q-bio.NC]; Neurobiologie

Francesco Petrelli, Glenn Dallérac, Luca Pucci, Corrado Calì, Tamara Zehnder, et al.. Dysfunction of homeostatic control of dopamine by astrocytes in the developing prefrontal cortex leads to cognitive impairments. Molecular Psychiatry, 2020, 25 (4), pp.732-749. ⟨10.1038/s41380-018-0226-y⟩. ⟨hal-02398206⟩