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Site-specific abnormalities in the visual system of a mouse model of CDKL5 deficiency disorder

CDKL5 deficiency disorder (CDD) is a neurodevelopmental disorder characterized by a severe global developmental delay and early-onset seizures. Notably, patients show distinctive visual abnormalities often clinically diagnosed as cortical visual impairment. However, the involvement of cerebral corti...

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Autores principales: Lupori, Leonardo, Sagona, Giulia, Fuchs, Claudia, Mazziotti, Raffaele, Stefanov, Antonia, Putignano, Elena, Napoli, Debora, Strettoi, Enrica, Ciani, Elisabetta, Pizzorusso, Tommaso
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736061/
https://www.ncbi.nlm.nih.gov/pubmed/31108505
http://dx.doi.org/10.1093/hmg/ddz102
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author Lupori, Leonardo
Sagona, Giulia
Fuchs, Claudia
Mazziotti, Raffaele
Stefanov, Antonia
Putignano, Elena
Napoli, Debora
Strettoi, Enrica
Ciani, Elisabetta
Pizzorusso, Tommaso
author_facet Lupori, Leonardo
Sagona, Giulia
Fuchs, Claudia
Mazziotti, Raffaele
Stefanov, Antonia
Putignano, Elena
Napoli, Debora
Strettoi, Enrica
Ciani, Elisabetta
Pizzorusso, Tommaso
author_sort Lupori, Leonardo
collection PubMed
description CDKL5 deficiency disorder (CDD) is a neurodevelopmental disorder characterized by a severe global developmental delay and early-onset seizures. Notably, patients show distinctive visual abnormalities often clinically diagnosed as cortical visual impairment. However, the involvement of cerebral cortical dysfunctions in the origin of the symptoms is poorly understood. CDD mouse models also display visual deficits, and cortical visual responses can be used as a robust biomarker in CDKL5 mutant mice. A deeper understanding of the circuits underlying the described visual deficits is essential for directing preclinical research and translational approaches. Here, we addressed this question in two ways: first, we performed an in-depth morphological analysis of the visual pathway, from the retina to the primary visual cortex (V1), of CDKL5 null mice. We found that the lack of CDKL5 produced no alteration in the organization of retinal circuits. Conversely, CDKL5 mutants showed reduced density and altered morphology of spines and decreased excitatory synapse marker PSD95 in the dorsal lateral geniculate nucleus and in V1. An increase in the inhibitory marker VGAT was selectively present in V1. Second, using a conditional CDKL5 knockout model, we showed that selective cortical deletion of CDKL5 from excitatory cells is sufficient to produce abnormalities of visual cortical responses, demonstrating that the normal function of cortical circuits is dependent on CDKL5. Intriguingly, these deficits were associated with morphological alterations of V1 excitatory and inhibitory synaptic contacts. In summary, this work proposes cortical circuit structure and function as a critically important target for studying CDD.
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spelling pubmed-67360612019-09-16 Site-specific abnormalities in the visual system of a mouse model of CDKL5 deficiency disorder Lupori, Leonardo Sagona, Giulia Fuchs, Claudia Mazziotti, Raffaele Stefanov, Antonia Putignano, Elena Napoli, Debora Strettoi, Enrica Ciani, Elisabetta Pizzorusso, Tommaso Hum Mol Genet General Article CDKL5 deficiency disorder (CDD) is a neurodevelopmental disorder characterized by a severe global developmental delay and early-onset seizures. Notably, patients show distinctive visual abnormalities often clinically diagnosed as cortical visual impairment. However, the involvement of cerebral cortical dysfunctions in the origin of the symptoms is poorly understood. CDD mouse models also display visual deficits, and cortical visual responses can be used as a robust biomarker in CDKL5 mutant mice. A deeper understanding of the circuits underlying the described visual deficits is essential for directing preclinical research and translational approaches. Here, we addressed this question in two ways: first, we performed an in-depth morphological analysis of the visual pathway, from the retina to the primary visual cortex (V1), of CDKL5 null mice. We found that the lack of CDKL5 produced no alteration in the organization of retinal circuits. Conversely, CDKL5 mutants showed reduced density and altered morphology of spines and decreased excitatory synapse marker PSD95 in the dorsal lateral geniculate nucleus and in V1. An increase in the inhibitory marker VGAT was selectively present in V1. Second, using a conditional CDKL5 knockout model, we showed that selective cortical deletion of CDKL5 from excitatory cells is sufficient to produce abnormalities of visual cortical responses, demonstrating that the normal function of cortical circuits is dependent on CDKL5. Intriguingly, these deficits were associated with morphological alterations of V1 excitatory and inhibitory synaptic contacts. In summary, this work proposes cortical circuit structure and function as a critically important target for studying CDD. Oxford University Press 2019-09-01 2019-04-24 /pmc/articles/PMC6736061/ /pubmed/31108505 http://dx.doi.org/10.1093/hmg/ddz102 Text en © The Author(s) 2019. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle General Article
Lupori, Leonardo
Sagona, Giulia
Fuchs, Claudia
Mazziotti, Raffaele
Stefanov, Antonia
Putignano, Elena
Napoli, Debora
Strettoi, Enrica
Ciani, Elisabetta
Pizzorusso, Tommaso
Site-specific abnormalities in the visual system of a mouse model of CDKL5 deficiency disorder
title Site-specific abnormalities in the visual system of a mouse model of CDKL5 deficiency disorder
title_full Site-specific abnormalities in the visual system of a mouse model of CDKL5 deficiency disorder
title_fullStr Site-specific abnormalities in the visual system of a mouse model of CDKL5 deficiency disorder
title_full_unstemmed Site-specific abnormalities in the visual system of a mouse model of CDKL5 deficiency disorder
title_short Site-specific abnormalities in the visual system of a mouse model of CDKL5 deficiency disorder
title_sort site-specific abnormalities in the visual system of a mouse model of cdkl5 deficiency disorder
topic General Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736061/
https://www.ncbi.nlm.nih.gov/pubmed/31108505
http://dx.doi.org/10.1093/hmg/ddz102
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