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Chemogenetic manipulation of astrocyte activity at the synapse— a gateway to manage brain disease

Astrocytes are the major glial cell type in the central nervous system (CNS). Initially regarded as supportive cells, it is now recognized that this highly heterogeneous cell population is an indispensable modulator of brain development and function. Astrocytes secrete neuroactive molecules that reg...

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Autores principales: Pereira, Maria João, Ayana, Rajagopal, Holt, Matthew G., Arckens, Lutgarde
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393042/
https://www.ncbi.nlm.nih.gov/pubmed/37534103
http://dx.doi.org/10.3389/fcell.2023.1193130
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author Pereira, Maria João
Ayana, Rajagopal
Holt, Matthew G.
Arckens, Lutgarde
author_facet Pereira, Maria João
Ayana, Rajagopal
Holt, Matthew G.
Arckens, Lutgarde
author_sort Pereira, Maria João
collection PubMed
description Astrocytes are the major glial cell type in the central nervous system (CNS). Initially regarded as supportive cells, it is now recognized that this highly heterogeneous cell population is an indispensable modulator of brain development and function. Astrocytes secrete neuroactive molecules that regulate synapse formation and maturation. They also express hundreds of G protein-coupled receptors (GPCRs) that, once activated by neurotransmitters, trigger intracellular signalling pathways that can trigger the release of gliotransmitters which, in turn, modulate synaptic transmission and neuroplasticity. Considering this, it is not surprising that astrocytic dysfunction, leading to synaptic impairment, is consistently described as a factor in brain diseases, whether they emerge early or late in life due to genetic or environmental factors. Here, we provide an overview of the literature showing that activation of genetically engineered GPCRs, known as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), to specifically modulate astrocyte activity partially mimics endogenous signalling pathways in astrocytes and improves neuronal function and behavior in normal animals and disease models. Therefore, we propose that expressing these genetically engineered GPCRs in astrocytes could be a promising strategy to explore (new) signalling pathways which can be used to manage brain disorders. The precise molecular, functional and behavioral effects of this type of manipulation, however, differ depending on the DREADD receptor used, targeted brain region and timing of the intervention, between healthy and disease conditions. This is likely a reflection of regional and disease/disease progression-associated astrocyte heterogeneity. Therefore, a thorough investigation of the effects of such astrocyte manipulation(s) must be conducted considering the specific cellular and molecular environment characteristic of each disease and disease stage before this has therapeutic applicability.
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spelling pubmed-103930422023-08-02 Chemogenetic manipulation of astrocyte activity at the synapse— a gateway to manage brain disease Pereira, Maria João Ayana, Rajagopal Holt, Matthew G. Arckens, Lutgarde Front Cell Dev Biol Cell and Developmental Biology Astrocytes are the major glial cell type in the central nervous system (CNS). Initially regarded as supportive cells, it is now recognized that this highly heterogeneous cell population is an indispensable modulator of brain development and function. Astrocytes secrete neuroactive molecules that regulate synapse formation and maturation. They also express hundreds of G protein-coupled receptors (GPCRs) that, once activated by neurotransmitters, trigger intracellular signalling pathways that can trigger the release of gliotransmitters which, in turn, modulate synaptic transmission and neuroplasticity. Considering this, it is not surprising that astrocytic dysfunction, leading to synaptic impairment, is consistently described as a factor in brain diseases, whether they emerge early or late in life due to genetic or environmental factors. Here, we provide an overview of the literature showing that activation of genetically engineered GPCRs, known as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), to specifically modulate astrocyte activity partially mimics endogenous signalling pathways in astrocytes and improves neuronal function and behavior in normal animals and disease models. Therefore, we propose that expressing these genetically engineered GPCRs in astrocytes could be a promising strategy to explore (new) signalling pathways which can be used to manage brain disorders. The precise molecular, functional and behavioral effects of this type of manipulation, however, differ depending on the DREADD receptor used, targeted brain region and timing of the intervention, between healthy and disease conditions. This is likely a reflection of regional and disease/disease progression-associated astrocyte heterogeneity. Therefore, a thorough investigation of the effects of such astrocyte manipulation(s) must be conducted considering the specific cellular and molecular environment characteristic of each disease and disease stage before this has therapeutic applicability. Frontiers Media S.A. 2023-07-18 /pmc/articles/PMC10393042/ /pubmed/37534103 http://dx.doi.org/10.3389/fcell.2023.1193130 Text en Copyright © 2023 Pereira, Ayana, Holt and Arckens. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Pereira, Maria João
Ayana, Rajagopal
Holt, Matthew G.
Arckens, Lutgarde
Chemogenetic manipulation of astrocyte activity at the synapse— a gateway to manage brain disease
title Chemogenetic manipulation of astrocyte activity at the synapse— a gateway to manage brain disease
title_full Chemogenetic manipulation of astrocyte activity at the synapse— a gateway to manage brain disease
title_fullStr Chemogenetic manipulation of astrocyte activity at the synapse— a gateway to manage brain disease
title_full_unstemmed Chemogenetic manipulation of astrocyte activity at the synapse— a gateway to manage brain disease
title_short Chemogenetic manipulation of astrocyte activity at the synapse— a gateway to manage brain disease
title_sort chemogenetic manipulation of astrocyte activity at the synapse— a gateway to manage brain disease
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393042/
https://www.ncbi.nlm.nih.gov/pubmed/37534103
http://dx.doi.org/10.3389/fcell.2023.1193130
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