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 Mothet; Paola Bezzi

doi:10.1038/s41380-018-0226-y

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

Biological, Environmental Sciences and Engineering

Research output: Contribution to journal › Article › peer-review

77 Scopus citations

Abstract

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 language	English (US)
Journal	Molecular Psychiatry
DOIs	https://doi.org/10.1038/s41380-018-0226-y
State	Published - 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.

Access to Document

10.1038/s41380-018-0226-y

https://repository.kaust.edu.sa/bitstream/10754/628466/1/s41380-018-0226-y.pdf

Cite this

Petrelli, F., Dallérac, G., Pucci, L., Cali, C., Zehnder, T., Sultan, S., Lecca, S., Chicca, A., Ivanov, A., Asensio, C. S., Gundersen, V., Toni, N., Knott, G. W., Magara, F., Gertsch, J., Kirchhoff, F., Déglon, N., Giros, B., Edwards, R. H., ... Bezzi, P. (2018). Dysfunction of homeostatic control of dopamine by astrocytes in the developing prefrontal cortex leads to cognitive impairments. Molecular Psychiatry. https://doi.org/10.1038/s41380-018-0226-y

@article{fe341cf1f8064c3abf5cdfb7ee275027,

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

abstract = "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.",

author = "Francesco Petrelli and Glenn Dall{\'e}rac and Luca Pucci and Corrado Cali and Tamara Zehnder and S{\'e}bastien Sultan and Salvatore Lecca and Andrea Chicca and Andrei Ivanov and Asensio, {C{\'e}dric S.} and Vidar Gundersen and Nicolas Toni and Knott, {Graham William} and Fulvio Magara and J{\"u}rg Gertsch and Frank Kirchhoff and Nicole D{\'e}glon and Bruno Giros and Edwards, {Robert H.} and Jean-Pierre Mothet and Paola Bezzi",

note = "KAUST Repository Item: Exported on 2020-10-01 Acknowledgements: We would like to thank G. Carmignoto and C. L{\"u}scher 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 M{\'e}dicale (Equipe FRM DEQ20150331734), CNRS, Universit{\'e} Aix-Marseille and Conseil R{\'e}gional Provence Alpes C{\^o}te d'Azur to JPM, and NSERC RGPIN grant 385732-2012 to B.G.",

year = "2018",

month = aug,

day = "20",

doi = "10.1038/s41380-018-0226-y",

language = "English (US)",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer Nature",

}

Petrelli, F, Dallérac, G, Pucci, L, Cali, C, Zehnder, T, Sultan, S, Lecca, S, Chicca, A, Ivanov, A, Asensio, CS, Gundersen, V, Toni, N, Knott, GW, Magara, F, Gertsch, J, Kirchhoff, F, Déglon, N, Giros, B, Edwards, RH, Mothet, J-P & Bezzi, P 2018, 'Dysfunction of homeostatic control of dopamine by astrocytes in the developing prefrontal cortex leads to cognitive impairments', Molecular Psychiatry. https://doi.org/10.1038/s41380-018-0226-y

TY - JOUR

T1 - Dysfunction of homeostatic control of dopamine by astrocytes in the developing prefrontal cortex leads to cognitive impairments

AU - Petrelli, Francesco

AU - Dallérac, Glenn

AU - Pucci, Luca

AU - Cali, Corrado

AU - Zehnder, Tamara

AU - Sultan, Sébastien

AU - Lecca, Salvatore

AU - Chicca, Andrea

AU - Ivanov, Andrei

AU - Asensio, Cédric S.

AU - Gundersen, Vidar

AU - Toni, Nicolas

AU - Knott, Graham William

AU - Magara, Fulvio

AU - Gertsch, Jürg

AU - Kirchhoff, Frank

AU - Déglon, Nicole

AU - Giros, Bruno

AU - Edwards, Robert H.

AU - Mothet, Jean-Pierre

AU - Bezzi, Paola

N1 - 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.

PY - 2018/8/20

Y1 - 2018/8/20

N2 - 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.

AB - 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.

UR - http://hdl.handle.net/10754/628466

UR - https://www.nature.com/articles/s41380-018-0226-y

UR - http://www.scopus.com/inward/record.url?scp=85052605677&partnerID=8YFLogxK

U2 - 10.1038/s41380-018-0226-y

DO - 10.1038/s41380-018-0226-y

M3 - Article

SN - 1359-4184

JO - Molecular Psychiatry

JF - Molecular Psychiatry

ER -

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

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this