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

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

doi:10.1038/s41380-018-0226-y

Cited by 92 publications

(100 citation statements)

References 86 publications

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“…Insulin signaling in hypothalamic astrocytes is a key component in glucose metabolism, with the genetic ablation of insulin receptors in mice leading to hyperphagia and impaired regulation of systemic glucose levels [99]. Finally, homeostatic control of dopamine levels by astrocytes in the prefrontal cortex is essential for synaptic transmission and plasticity, playing a crucial role in memory and behavioral flexibility [100]. Likewise, the activation of astrocytes (but not neurons) in hippocampal CA1, using a Gq-coupled DREADD, was shown to enhance memory acquisition in mice [101].…”

Section: Functional Heterogeneitymentioning

confidence: 99%

No Longer Underappreciated: The Emerging Concept of Astrocyte Heterogeneity in Neuroscience

Pestana

Edwards-Faret

Belgard³

et al. 2020

Brain Sciences

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Astrocytes are ubiquitous in the central nervous system (CNS). These cells possess thousands of individual processes, which extend out into the neuropil, interacting with neurons, other glia and blood vessels. Paralleling the wide diversity of their interactions, astrocytes have been reported to play key roles in supporting CNS structure, metabolism, blood-brain-barrier formation and control of vascular blood flow, axon guidance, synapse formation and modulation of synaptic transmission. Traditionally, astrocytes have been studied as a homogenous group of cells. However, recent studies have uncovered a surprising degree of heterogeneity in their development and function, in both the healthy and diseased brain. A better understanding of astrocyte heterogeneity is urgently needed to understand normal brain function, as well as the role of astrocytes in response to injury and disease.

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Section: Functional Heterogeneitymentioning

confidence: 99%

No Longer Underappreciated: The Emerging Concept of Astrocyte Heterogeneity in Neuroscience

Pestana

Edwards-Faret

Belgard³

et al. 2020

Brain Sciences

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“…By releasing glutamate, D-serine, GABA, ATP, adenosine, or tumor necrosis factor-alpha, among others, astrocytes control the basal tone of synaptic activity and the threshold for synaptic plasticity (Beattie et al, 2002 ; Angulo et al, 2004 ; Fellin et al, 2004 ; Jourdain et al, 2007 ; Perea and Araque, 2007 ; Henneberger et al, 2010 ; Bonansco et al, 2011 ; Di Castro et al, 2011 ; Panatier et al, 2011 ; Chen et al, 2013 ; Shigetomi et al, 2013 ; Gómez-Gonzalo et al, 2015 ; De Pittà and Brunel, 2016 ; Petrelli et al, 2018 ). One hippocampal astrocyte ensheaths approximately 120,000 synapses (Bushong et al, 2002 ) belonging to different cell types (excitatory vs. inhibitory neurons) and circuits, and that astrocyte might be able to detect the NTs released from all of those synapses.…”

Section: Astrocytes: Master Regulators Of Synaptic Activitymentioning

confidence: 99%

Astrocyte–Neuron Networks: A Multilane Highway of Signaling for Homeostatic Brain Function

Mederos

González-Arias

Perea

2018

Front. Synaptic Neurosci.

128

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Research on glial cells over the past 30 years has confirmed the critical role of astrocytes in pathophysiological brain states. However, most of our knowledge about astrocyte physiology and of the interactions between astrocytes and neurons is based on the premises that astrocytes constitute a homogeneous cell type, without considering the particular properties of the circuits or brain nuclei in which the astrocytes are located. Therefore, we argue that more-sophisticated experiments are required to elucidate the specific features of astrocytes in different brain regions, and even within different layers of a particular circuit. Thus, in addition to considering the diverse mechanisms used by astrocytes to communicate with neurons and synaptic partners, it is necessary to take into account the cellular heterogeneity that likely contributes to the outcomes of astrocyte–neuron signaling. In this review article, we briefly summarize the current data regarding the anatomical, molecular and functional properties of astrocyte–neuron communication, as well as the heterogeneity within this communication.

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“…Of note, ME2 and NE8 carry an allele of the variable number tandem repeat (VNTR) polymorphism in the MAOA promoter region associated with high gene expression (36,37), whereas control-1, control-2 and ME8 carry an allele associated with low expression ( Supplementary Figure 2). These alleles have previously been suggested to affect MAOA expression differentially using luciferase assays in immortalized cell lines (38).…”

Section: Generation Of Da Neurons Derived From Individuals With and Wmentioning

confidence: 98%

Brunner syndrome associated MAOA dysfunction in human dopaminergic neurons results in NMDAR hyperfunction and increased network activity

Shi

Rhijn

Bormann

et al. 2020

Preprint

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Background: Monoamine neurotransmitter abundance affects motor control, emotion, and cognitive function and is regulated by monoamine oxidases. Amongst these, monoamine oxidase A (MAOA) catalyzes the degradation of dopamine, norepinephrine, and serotonin into their inactive metabolites. Loss-of-function mutations in the X-linked MAOA gene cause Brunner syndrome, which is characterized by various forms of impulsivity, maladaptive externalizing behavior, and mild intellectual disability. Impaired MAOA activity in individuals with Brunner syndrome results in bioamine aberration, but it is currently unknown how this affects neuronal function. Methods: We generated human induced pluripotent stem cell (hiPSC)-derived dopaminergic (DA) neurons from three individuals with Brunner syndrome carrying different mutations, and used CRISPR/Cas9 mediated homologous recombination to rescue MAOA function. We used these lines to characterize morphological and functional properties of DA neuronal cultures at the single cell and neuronal network level in vitro. Results: Brunner syndrome DA neurons showed reduced synaptic density but hyperactive network activity. Intrinsic functional properties and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission were not affected by MAOA dysfunction. Instead, we show that the neuronal network hyperactivity is mediated by upregulation of the GRIN2A and GRIN2B subunits of the N-methyl-D-aspartate receptor (NMDAR), and rescue of MAOA results in normalization of NMDAR function as well as restoration of network activity. Conclusions: Our data suggest that MAOA dysfunction in Brunner syndrome increases activity of dopaminergic neurons through upregulation of NMDAR function, which may contribute to Brunner syndrome associated phenotypes.

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

Cited by 92 publications

References 86 publications

No Longer Underappreciated: The Emerging Concept of Astrocyte Heterogeneity in Neuroscience

No Longer Underappreciated: The Emerging Concept of Astrocyte Heterogeneity in Neuroscience

Astrocyte–Neuron Networks: A Multilane Highway of Signaling for Homeostatic Brain Function

Brunner syndrome associated MAOA dysfunction in human dopaminergic neurons results in NMDAR hyperfunction and increased network activity

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