Disruption of extracellular matrix and perineuronal nets modulates extracellular space volume and geometry

Autores
Syková, Eva; Voříek, Ivan; Starčuk, Zenon; Kratochvíla, Jiří; Pavlova, Iveta; Ichikawa, Yuki; Kwok, Jessica C.F.; Kmoníčková, Eva; Myronchenko, Svitlana; Hromádka, Tomás; Smolek, Tomás; Avila, Martin; Basheer, Neha; Zilka, Norbert
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Extracellular matrix (ECM) is a network of macromolecules which has two forms - perineuronal nets (PNNs) and a diffuse ECM (dECM) - both influence brain development, synapse formation, neuroplasticity, CNS injury and progression of neurodegenerative diseases. ECM remodeling can influence extrasynaptic transmission, mediated by diffusion of neuroactive substances in the extracellular space (ECS). In this study we analyzed how disrupted PNNs and dECM influence brain diffusibility. Two months after oral treatment of rats with 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan synthesis, we found downregulated staining for PNNs, hyaluronan, chondroitin sulphate proteoglycans and glial fibrillary acidic protein (GFAP). These changes were enhanced after 4 and 6 months and were reversible after normal diet. Morphometric analysis further indicated atrophy of astrocytes. Using real-time iontophoretic method dysregulation of ECM resulted in increased ECS volume fraction α in somatosensory cortex (SC) by 35 %, from α = 0.20 in control rats to α = 0.27 after the 4-MU diet. Diffusion-weighted magnetic resonance imaging (DW-MRI) revealed a decrease of mean diffusivity (MD) and fractional anisotropy (FA) in the cortex, hippocampus, thalamus, pallidum and spinal cord. This study shows the increase in ECS volume, a loss of FA and changes in astrocytes due to modulation of PNNs and dECM that could affect extrasynaptic transmission, cell to cell communication and neural plasticity. Significance Statement Inhibition of hyaluronan synthesis induced by oral treatment with 4-methylumebelliferone disrupts perineuronal nets (PNNs), diffuse extracellular matrix (dECM), reduces the astrocytic network, increases extracellular space (ECS) volume and changes ECS geometry. The changes of diffusion barriers significantly affect diffusion parameters in the adult brain and spinal cord. Our findings suggest that disruption of ECM allows for more efficient transport of ions, neurotransmitters and neuroactive substances in the ECS and thus ensures broader inter-neuronal communication by extrasynaptic transmission. Disruption of PNNs and an increase in ECS volume can result in enhanced crosstalk between synapses, spill-over of transmitters, formation of new synaptic contacts and thus increased synaptic plasticity.
Fil: Syková, Eva. Slovak Academy of Science. Institute of Neuroimmunology; Eslovaquia
Fil: Voříek, Ivan. Slovak Academy of Science. Institute of Neuroimmunology; Eslovaquia
Fil: Starčuk, Zenon. Czech Academy of Sciences; República Checa
Fil: Kratochvíla, Jiří. Czech Academy of Sciences; República Checa
Fil: Pavlova, Iveta. Czech Academy of Sciences; República Checa
Fil: Ichikawa, Yuki. University of Leeds; Reino Unido
Fil: Kwok, Jessica C.F.. University of Leeds; Reino Unido
Fil: Kmoníčková, Eva. Karlova Univerzita; República Checa
Fil: Myronchenko, Svitlana. Karlova Univerzita; República Checa
Fil: Hromádka, Tomás. Slovak Academy of Science; Eslovaquia
Fil: Smolek, Tomás. Slovak Academy of Science; Eslovaquia
Fil: Avila, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Basheer, Neha. Slovak Academy Of Science, Institute Of Neuroimmunology; Eslovaquia
Fil: Zilka, Norbert. Slovak Academy Of Science, Institute Of Neuroimmunology; Eslovaquia
Materia
EXTRACELLULAR DIFFUSION
PLASTICITY
EXTRACELLULAR MATRIX
PERINEURONAL NETS
EXTRACELLULAR TRANSMISSION
HYALURONAN SYNTHASE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/290777
Acceder
id CONICETDig_982dcbf482129a2ca22bfc1622428e6b
oai_identifier_str oai:ri.conicet.gov.ar:11336/290777
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Disruption of extracellular matrix and perineuronal nets modulates extracellular space volume and geometrySyková, EvaVoříek, IvanStarčuk, ZenonKratochvíla, JiříPavlova, IvetaIchikawa, YukiKwok, Jessica C.F.Kmoníčková, EvaMyronchenko, SvitlanaHromádka, TomásSmolek, TomásAvila, MartinBasheer, NehaZilka, NorbertEXTRACELLULAR DIFFUSIONPLASTICITYEXTRACELLULAR MATRIXPERINEURONAL NETSEXTRACELLULAR TRANSMISSIONHYALURONAN SYNTHASEhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Extracellular matrix (ECM) is a network of macromolecules which has two forms - perineuronal nets (PNNs) and a diffuse ECM (dECM) - both influence brain development, synapse formation, neuroplasticity, CNS injury and progression of neurodegenerative diseases. ECM remodeling can influence extrasynaptic transmission, mediated by diffusion of neuroactive substances in the extracellular space (ECS). In this study we analyzed how disrupted PNNs and dECM influence brain diffusibility. Two months after oral treatment of rats with 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan synthesis, we found downregulated staining for PNNs, hyaluronan, chondroitin sulphate proteoglycans and glial fibrillary acidic protein (GFAP). These changes were enhanced after 4 and 6 months and were reversible after normal diet. Morphometric analysis further indicated atrophy of astrocytes. Using real-time iontophoretic method dysregulation of ECM resulted in increased ECS volume fraction α in somatosensory cortex (SC) by 35 %, from α = 0.20 in control rats to α = 0.27 after the 4-MU diet. Diffusion-weighted magnetic resonance imaging (DW-MRI) revealed a decrease of mean diffusivity (MD) and fractional anisotropy (FA) in the cortex, hippocampus, thalamus, pallidum and spinal cord. This study shows the increase in ECS volume, a loss of FA and changes in astrocytes due to modulation of PNNs and dECM that could affect extrasynaptic transmission, cell to cell communication and neural plasticity. Significance Statement Inhibition of hyaluronan synthesis induced by oral treatment with 4-methylumebelliferone disrupts perineuronal nets (PNNs), diffuse extracellular matrix (dECM), reduces the astrocytic network, increases extracellular space (ECS) volume and changes ECS geometry. The changes of diffusion barriers significantly affect diffusion parameters in the adult brain and spinal cord. Our findings suggest that disruption of ECM allows for more efficient transport of ions, neurotransmitters and neuroactive substances in the ECS and thus ensures broader inter-neuronal communication by extrasynaptic transmission. Disruption of PNNs and an increase in ECS volume can result in enhanced crosstalk between synapses, spill-over of transmitters, formation of new synaptic contacts and thus increased synaptic plasticity.Fil: Syková, Eva. Slovak Academy of Science. Institute of Neuroimmunology; EslovaquiaFil: Voříek, Ivan. Slovak Academy of Science. Institute of Neuroimmunology; EslovaquiaFil: Starčuk, Zenon. Czech Academy of Sciences; República ChecaFil: Kratochvíla, Jiří. Czech Academy of Sciences; República ChecaFil: Pavlova, Iveta. Czech Academy of Sciences; República ChecaFil: Ichikawa, Yuki. University of Leeds; Reino UnidoFil: Kwok, Jessica C.F.. University of Leeds; Reino UnidoFil: Kmoníčková, Eva. Karlova Univerzita; República ChecaFil: Myronchenko, Svitlana. Karlova Univerzita; República ChecaFil: Hromádka, Tomás. Slovak Academy of Science; EslovaquiaFil: Smolek, Tomás. Slovak Academy of Science; EslovaquiaFil: Avila, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Basheer, Neha. Slovak Academy Of Science, Institute Of Neuroimmunology; EslovaquiaFil: Zilka, Norbert. Slovak Academy Of Science, Institute Of Neuroimmunology; EslovaquiaSociety for Neuroscience2025-01-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/290777Syková, Eva; Voříek, Ivan; Starčuk, Zenon ; Kratochvíla, Jiří; Pavlova, Iveta; et al.; Disruption of extracellular matrix and perineuronal nets modulates extracellular space volume and geometry; Society for Neuroscience; Journal of Neuroscience; 45; 8; 3-1-2025; 1-140270-6474CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.jneurosci.org/lookup/doi/10.1523/JNEUROSCI.0517-24.2024info:eu-repo/semantics/altIdentifier/doi/10.1523/JNEUROSCI.0517-24.2024info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-08-25T15:11:38Zoai:ri.conicet.gov.ar:11336/290777instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982026-08-25 15:11:38.693CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Disruption of extracellular matrix and perineuronal nets modulates extracellular space volume and geometry
title Disruption of extracellular matrix and perineuronal nets modulates extracellular space volume and geometry
spellingShingle Disruption of extracellular matrix and perineuronal nets modulates extracellular space volume and geometry
Syková, Eva
EXTRACELLULAR DIFFUSION
PLASTICITY
EXTRACELLULAR MATRIX
PERINEURONAL NETS
EXTRACELLULAR TRANSMISSION
HYALURONAN SYNTHASE
title_short Disruption of extracellular matrix and perineuronal nets modulates extracellular space volume and geometry
title_full Disruption of extracellular matrix and perineuronal nets modulates extracellular space volume and geometry
title_fullStr Disruption of extracellular matrix and perineuronal nets modulates extracellular space volume and geometry
title_full_unstemmed Disruption of extracellular matrix and perineuronal nets modulates extracellular space volume and geometry
title_sort Disruption of extracellular matrix and perineuronal nets modulates extracellular space volume and geometry
dc.creator.none.fl_str_mv Syková, Eva
Voříek, Ivan
Starčuk, Zenon
Kratochvíla, Jiří
Pavlova, Iveta
Ichikawa, Yuki
Kwok, Jessica C.F.
Kmoníčková, Eva
Myronchenko, Svitlana
Hromádka, Tomás
Smolek, Tomás
Avila, Martin
Basheer, Neha
Zilka, Norbert
author Syková, Eva
author_facet Syková, Eva
Voříek, Ivan
Starčuk, Zenon
Kratochvíla, Jiří
Pavlova, Iveta
Ichikawa, Yuki
Kwok, Jessica C.F.
Kmoníčková, Eva
Myronchenko, Svitlana
Hromádka, Tomás
Smolek, Tomás
Avila, Martin
Basheer, Neha
Zilka, Norbert
author_role author
author2 Voříek, Ivan
Starčuk, Zenon
Kratochvíla, Jiří
Pavlova, Iveta
Ichikawa, Yuki
Kwok, Jessica C.F.
Kmoníčková, Eva
Myronchenko, Svitlana
Hromádka, Tomás
Smolek, Tomás
Avila, Martin
Basheer, Neha
Zilka, Norbert
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv EXTRACELLULAR DIFFUSION
PLASTICITY
EXTRACELLULAR MATRIX
PERINEURONAL NETS
EXTRACELLULAR TRANSMISSION
HYALURONAN SYNTHASE
topic EXTRACELLULAR DIFFUSION
PLASTICITY
EXTRACELLULAR MATRIX
PERINEURONAL NETS
EXTRACELLULAR TRANSMISSION
HYALURONAN SYNTHASE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Extracellular matrix (ECM) is a network of macromolecules which has two forms - perineuronal nets (PNNs) and a diffuse ECM (dECM) - both influence brain development, synapse formation, neuroplasticity, CNS injury and progression of neurodegenerative diseases. ECM remodeling can influence extrasynaptic transmission, mediated by diffusion of neuroactive substances in the extracellular space (ECS). In this study we analyzed how disrupted PNNs and dECM influence brain diffusibility. Two months after oral treatment of rats with 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan synthesis, we found downregulated staining for PNNs, hyaluronan, chondroitin sulphate proteoglycans and glial fibrillary acidic protein (GFAP). These changes were enhanced after 4 and 6 months and were reversible after normal diet. Morphometric analysis further indicated atrophy of astrocytes. Using real-time iontophoretic method dysregulation of ECM resulted in increased ECS volume fraction α in somatosensory cortex (SC) by 35 %, from α = 0.20 in control rats to α = 0.27 after the 4-MU diet. Diffusion-weighted magnetic resonance imaging (DW-MRI) revealed a decrease of mean diffusivity (MD) and fractional anisotropy (FA) in the cortex, hippocampus, thalamus, pallidum and spinal cord. This study shows the increase in ECS volume, a loss of FA and changes in astrocytes due to modulation of PNNs and dECM that could affect extrasynaptic transmission, cell to cell communication and neural plasticity. Significance Statement Inhibition of hyaluronan synthesis induced by oral treatment with 4-methylumebelliferone disrupts perineuronal nets (PNNs), diffuse extracellular matrix (dECM), reduces the astrocytic network, increases extracellular space (ECS) volume and changes ECS geometry. The changes of diffusion barriers significantly affect diffusion parameters in the adult brain and spinal cord. Our findings suggest that disruption of ECM allows for more efficient transport of ions, neurotransmitters and neuroactive substances in the ECS and thus ensures broader inter-neuronal communication by extrasynaptic transmission. Disruption of PNNs and an increase in ECS volume can result in enhanced crosstalk between synapses, spill-over of transmitters, formation of new synaptic contacts and thus increased synaptic plasticity.
Fil: Syková, Eva. Slovak Academy of Science. Institute of Neuroimmunology; Eslovaquia
Fil: Voříek, Ivan. Slovak Academy of Science. Institute of Neuroimmunology; Eslovaquia
Fil: Starčuk, Zenon. Czech Academy of Sciences; República Checa
Fil: Kratochvíla, Jiří. Czech Academy of Sciences; República Checa
Fil: Pavlova, Iveta. Czech Academy of Sciences; República Checa
Fil: Ichikawa, Yuki. University of Leeds; Reino Unido
Fil: Kwok, Jessica C.F.. University of Leeds; Reino Unido
Fil: Kmoníčková, Eva. Karlova Univerzita; República Checa
Fil: Myronchenko, Svitlana. Karlova Univerzita; República Checa
Fil: Hromádka, Tomás. Slovak Academy of Science; Eslovaquia
Fil: Smolek, Tomás. Slovak Academy of Science; Eslovaquia
Fil: Avila, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Basheer, Neha. Slovak Academy Of Science, Institute Of Neuroimmunology; Eslovaquia
Fil: Zilka, Norbert. Slovak Academy Of Science, Institute Of Neuroimmunology; Eslovaquia
description Extracellular matrix (ECM) is a network of macromolecules which has two forms - perineuronal nets (PNNs) and a diffuse ECM (dECM) - both influence brain development, synapse formation, neuroplasticity, CNS injury and progression of neurodegenerative diseases. ECM remodeling can influence extrasynaptic transmission, mediated by diffusion of neuroactive substances in the extracellular space (ECS). In this study we analyzed how disrupted PNNs and dECM influence brain diffusibility. Two months after oral treatment of rats with 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan synthesis, we found downregulated staining for PNNs, hyaluronan, chondroitin sulphate proteoglycans and glial fibrillary acidic protein (GFAP). These changes were enhanced after 4 and 6 months and were reversible after normal diet. Morphometric analysis further indicated atrophy of astrocytes. Using real-time iontophoretic method dysregulation of ECM resulted in increased ECS volume fraction α in somatosensory cortex (SC) by 35 %, from α = 0.20 in control rats to α = 0.27 after the 4-MU diet. Diffusion-weighted magnetic resonance imaging (DW-MRI) revealed a decrease of mean diffusivity (MD) and fractional anisotropy (FA) in the cortex, hippocampus, thalamus, pallidum and spinal cord. This study shows the increase in ECS volume, a loss of FA and changes in astrocytes due to modulation of PNNs and dECM that could affect extrasynaptic transmission, cell to cell communication and neural plasticity. Significance Statement Inhibition of hyaluronan synthesis induced by oral treatment with 4-methylumebelliferone disrupts perineuronal nets (PNNs), diffuse extracellular matrix (dECM), reduces the astrocytic network, increases extracellular space (ECS) volume and changes ECS geometry. The changes of diffusion barriers significantly affect diffusion parameters in the adult brain and spinal cord. Our findings suggest that disruption of ECM allows for more efficient transport of ions, neurotransmitters and neuroactive substances in the ECS and thus ensures broader inter-neuronal communication by extrasynaptic transmission. Disruption of PNNs and an increase in ECS volume can result in enhanced crosstalk between synapses, spill-over of transmitters, formation of new synaptic contacts and thus increased synaptic plasticity.
publishDate 2025
dc.date.none.fl_str_mv 2025-01-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/290777
Syková, Eva; Voříek, Ivan; Starčuk, Zenon ; Kratochvíla, Jiří; Pavlova, Iveta; et al.; Disruption of extracellular matrix and perineuronal nets modulates extracellular space volume and geometry; Society for Neuroscience; Journal of Neuroscience; 45; 8; 3-1-2025; 1-14
0270-6474
CONICET Digital
CONICET
url http://hdl.handle.net/11336/290777
identifier_str_mv Syková, Eva; Voříek, Ivan; Starčuk, Zenon ; Kratochvíla, Jiří; Pavlova, Iveta; et al.; Disruption of extracellular matrix and perineuronal nets modulates extracellular space volume and geometry; Society for Neuroscience; Journal of Neuroscience; 45; 8; 3-1-2025; 1-14
0270-6474
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.jneurosci.org/lookup/doi/10.1523/JNEUROSCI.0517-24.2024
info:eu-repo/semantics/altIdentifier/doi/10.1523/JNEUROSCI.0517-24.2024
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Society for Neuroscience
publisher.none.fl_str_mv Society for Neuroscience
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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