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Chronic Chemogenetic Activation of the Superior Colliculus in Glaucomatous Mice: Local and Retrograde Molecular Signature

One important facet of glaucoma pathophysiology is axonal damage, which ultimately disrupts the connection between the retina and its postsynaptic brain targets. The concurrent loss of retrograde support interferes with the functionality and survival of the retinal ganglion cells (RGCs). Previous re...

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Autores principales: Claes, Marie, Geeraerts, Emiel, Plaisance, Stéphane, Mentens, Stephanie, Van den Haute, Chris, De Groef, Lies, Arckens, Lut, Moons, Lieve
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9179903/
https://www.ncbi.nlm.nih.gov/pubmed/35681479
http://dx.doi.org/10.3390/cells11111784
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author Claes, Marie
Geeraerts, Emiel
Plaisance, Stéphane
Mentens, Stephanie
Van den Haute, Chris
De Groef, Lies
Arckens, Lut
Moons, Lieve
author_facet Claes, Marie
Geeraerts, Emiel
Plaisance, Stéphane
Mentens, Stephanie
Van den Haute, Chris
De Groef, Lies
Arckens, Lut
Moons, Lieve
author_sort Claes, Marie
collection PubMed
description One important facet of glaucoma pathophysiology is axonal damage, which ultimately disrupts the connection between the retina and its postsynaptic brain targets. The concurrent loss of retrograde support interferes with the functionality and survival of the retinal ganglion cells (RGCs). Previous research has shown that stimulation of neuronal activity in a primary retinal target area—i.e., the superior colliculus—promotes RGC survival in an acute mouse model of glaucoma. To build further on this observation, we applied repeated chemogenetics in the superior colliculus of a more chronic murine glaucoma model—i.e., the microbead occlusion model—and performed bulk RNA sequencing on collicular lysates and isolated RGCs. Our study revealed that chronic target stimulation upon glaucomatous injury phenocopies the a priori expected molecular response: growth factors were pinpointed as essential transcriptional regulators both in the locally stimulated tissue and in distant, unstimulated RGCs. Strikingly, and although the RGC transcriptome revealed a partial reversal of the glaucomatous signature and an enrichment of pro-survival signaling pathways, functional rescue of injured RGCs was not achieved. By postulating various explanations for the lack of RGC neuroprotection, we aim to warrant researchers and drug developers for the complexity of chronic neuromodulation and growth factor signaling.
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spelling pubmed-91799032022-06-10 Chronic Chemogenetic Activation of the Superior Colliculus in Glaucomatous Mice: Local and Retrograde Molecular Signature Claes, Marie Geeraerts, Emiel Plaisance, Stéphane Mentens, Stephanie Van den Haute, Chris De Groef, Lies Arckens, Lut Moons, Lieve Cells Article One important facet of glaucoma pathophysiology is axonal damage, which ultimately disrupts the connection between the retina and its postsynaptic brain targets. The concurrent loss of retrograde support interferes with the functionality and survival of the retinal ganglion cells (RGCs). Previous research has shown that stimulation of neuronal activity in a primary retinal target area—i.e., the superior colliculus—promotes RGC survival in an acute mouse model of glaucoma. To build further on this observation, we applied repeated chemogenetics in the superior colliculus of a more chronic murine glaucoma model—i.e., the microbead occlusion model—and performed bulk RNA sequencing on collicular lysates and isolated RGCs. Our study revealed that chronic target stimulation upon glaucomatous injury phenocopies the a priori expected molecular response: growth factors were pinpointed as essential transcriptional regulators both in the locally stimulated tissue and in distant, unstimulated RGCs. Strikingly, and although the RGC transcriptome revealed a partial reversal of the glaucomatous signature and an enrichment of pro-survival signaling pathways, functional rescue of injured RGCs was not achieved. By postulating various explanations for the lack of RGC neuroprotection, we aim to warrant researchers and drug developers for the complexity of chronic neuromodulation and growth factor signaling. MDPI 2022-05-29 /pmc/articles/PMC9179903/ /pubmed/35681479 http://dx.doi.org/10.3390/cells11111784 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Claes, Marie
Geeraerts, Emiel
Plaisance, Stéphane
Mentens, Stephanie
Van den Haute, Chris
De Groef, Lies
Arckens, Lut
Moons, Lieve
Chronic Chemogenetic Activation of the Superior Colliculus in Glaucomatous Mice: Local and Retrograde Molecular Signature
title Chronic Chemogenetic Activation of the Superior Colliculus in Glaucomatous Mice: Local and Retrograde Molecular Signature
title_full Chronic Chemogenetic Activation of the Superior Colliculus in Glaucomatous Mice: Local and Retrograde Molecular Signature
title_fullStr Chronic Chemogenetic Activation of the Superior Colliculus in Glaucomatous Mice: Local and Retrograde Molecular Signature
title_full_unstemmed Chronic Chemogenetic Activation of the Superior Colliculus in Glaucomatous Mice: Local and Retrograde Molecular Signature
title_short Chronic Chemogenetic Activation of the Superior Colliculus in Glaucomatous Mice: Local and Retrograde Molecular Signature
title_sort chronic chemogenetic activation of the superior colliculus in glaucomatous mice: local and retrograde molecular signature
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9179903/
https://www.ncbi.nlm.nih.gov/pubmed/35681479
http://dx.doi.org/10.3390/cells11111784
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