Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability

Background Cellular prion protein (PrP(C)) is a cell surface GPI-anchored protein, usually known for its role in the pathogenesis of human and animal prionopathies. However, increasing knowledge about the participation of PrP(C) in prion pathogenesis contrasts with puzzling data regarding its natura...

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Autores: Matamoros i Anglès, Andreu, Hervera Abad, Arnau, Soriano i Fradera, Jordi, Martí Puig, Eulàlia, Carulla Martí, Patricia, Llorens Torres, Franc, Nuvolone, Mario, Aguzzi, Adriano, Ferrer, Isidro (Ferrer Abizanda), Gruart i Massó, Agnès, Delgado García, José M., Río Fernández, José Antonio del
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2022
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositório:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/182571
Acesso em linha:https://hdl.handle.net/2445/182571
Access Level:Acceso aberto
Palavra-chave:Glicoproteïnes
Hipocamp (Cervell)
Glycoproteins
Hippocampus (Brain)
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spelling Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitabilityMatamoros i Anglès, AndreuHervera Abad, ArnauSoriano i Fradera, JordiMartí Puig, EulàliaCarulla Martí, PatriciaLlorens Torres, FrancNuvolone, MarioAguzzi, AdrianoFerrer, Isidro (Ferrer Abizanda)Gruart i Massó, AgnèsDelgado García, José M.Río Fernández, José Antonio delGlicoproteïnesHipocamp (Cervell)GlycoproteinsHippocampus (Brain)Background Cellular prion protein (PrP(C)) is a cell surface GPI-anchored protein, usually known for its role in the pathogenesis of human and animal prionopathies. However, increasing knowledge about the participation of PrP(C) in prion pathogenesis contrasts with puzzling data regarding its natural physiological role. PrP(C) is expressed in a number of tissues, including at high levels in the nervous system, especially in neurons and glial cells, and while previous studies have established a neuroprotective role, conflicting evidence for a synaptic function has revealed both reduced and enhanced long-term potentiation, and variable observations on memory, learning, and behavior. Such evidence has been confounded by the absence of an appropriate knock-out mouse model to dissect the biological relevance of PrP(C), with some functions recently shown to be misattributed to PrP(C) due to the presence of genetic artifacts in mouse models. Here we elucidate the role of PrP(C) in the hippocampal circuitry and its related functions, such as learning and memory, using a recently available strictly co-isogenic Prnp(0/0) mouse model (Prnp(ZH3/ZH3)). Results We performed behavioral and operant conditioning tests to evaluate memory and learning capabilities, with results showing decreased motility, impaired operant conditioning learning, and anxiety-related behavior in Prnp(ZH3/ZH3) animals. We also carried in vivo electrophysiological recordings on CA3-CA1 synapses in living behaving mice and monitored spontaneous neuronal firing and network formation in primary neuronal cultures of Prnp(ZH3/ZH3) vs wildtype mice. PrP(C) absence enhanced susceptibility to high-intensity stimulations and kainate-induced seizures. However, long-term potentiation (LTP) was not enhanced in the Prnp(ZH3/ZH3) hippocampus. In addition, we observed a delay in neuronal maturation and network formation in Prnp(ZH3/ZH3) cultures. Conclusion Our results demonstrate that PrP(C) promotes neuronal network formation and connectivity. PrP(C) mediates synaptic function and protects the synapse from excitotoxic insults. Its deletion may underlie an epileptogenic-susceptible brain that fails to perform highly cognitive-demanding tasks such as associative learning and anxiety-like behaviors.BioMed Central2022202220222022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion25 p.application/pdfhttps://hdl.handle.net/2445/182571Articles publicats en revistes (Biomedicina)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1186/s12915-021-01203-0Bmc Biology, 2022, vol. 20, num. 1https://doi.org/10.1186/s12915-021-01203-0info:eu-repo/grantAgreement/EC/H2020/713140cc-by (c) Matamoros i Anglès, Andreu et al., 2022https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1825712026-05-29T05:05:01Z
dc.title.none.fl_str_mv Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability
title Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability
spellingShingle Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability
Matamoros i Anglès, Andreu
Glicoproteïnes
Hipocamp (Cervell)
Glycoproteins
Hippocampus (Brain)
title_short Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability
title_full Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability
title_fullStr Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability
title_full_unstemmed Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability
title_sort Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability
dc.creator.none.fl_str_mv Matamoros i Anglès, Andreu
Hervera Abad, Arnau
Soriano i Fradera, Jordi
Martí Puig, Eulàlia
Carulla Martí, Patricia
Llorens Torres, Franc
Nuvolone, Mario
Aguzzi, Adriano
Ferrer, Isidro (Ferrer Abizanda)
Gruart i Massó, Agnès
Delgado García, José M.
Río Fernández, José Antonio del
author Matamoros i Anglès, Andreu
author_facet Matamoros i Anglès, Andreu
Hervera Abad, Arnau
Soriano i Fradera, Jordi
Martí Puig, Eulàlia
Carulla Martí, Patricia
Llorens Torres, Franc
Nuvolone, Mario
Aguzzi, Adriano
Ferrer, Isidro (Ferrer Abizanda)
Gruart i Massó, Agnès
Delgado García, José M.
Río Fernández, José Antonio del
author_role author
author2 Hervera Abad, Arnau
Soriano i Fradera, Jordi
Martí Puig, Eulàlia
Carulla Martí, Patricia
Llorens Torres, Franc
Nuvolone, Mario
Aguzzi, Adriano
Ferrer, Isidro (Ferrer Abizanda)
Gruart i Massó, Agnès
Delgado García, José M.
Río Fernández, José Antonio del
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Glicoproteïnes
Hipocamp (Cervell)
Glycoproteins
Hippocampus (Brain)
topic Glicoproteïnes
Hipocamp (Cervell)
Glycoproteins
Hippocampus (Brain)
description Background Cellular prion protein (PrP(C)) is a cell surface GPI-anchored protein, usually known for its role in the pathogenesis of human and animal prionopathies. However, increasing knowledge about the participation of PrP(C) in prion pathogenesis contrasts with puzzling data regarding its natural physiological role. PrP(C) is expressed in a number of tissues, including at high levels in the nervous system, especially in neurons and glial cells, and while previous studies have established a neuroprotective role, conflicting evidence for a synaptic function has revealed both reduced and enhanced long-term potentiation, and variable observations on memory, learning, and behavior. Such evidence has been confounded by the absence of an appropriate knock-out mouse model to dissect the biological relevance of PrP(C), with some functions recently shown to be misattributed to PrP(C) due to the presence of genetic artifacts in mouse models. Here we elucidate the role of PrP(C) in the hippocampal circuitry and its related functions, such as learning and memory, using a recently available strictly co-isogenic Prnp(0/0) mouse model (Prnp(ZH3/ZH3)). Results We performed behavioral and operant conditioning tests to evaluate memory and learning capabilities, with results showing decreased motility, impaired operant conditioning learning, and anxiety-related behavior in Prnp(ZH3/ZH3) animals. We also carried in vivo electrophysiological recordings on CA3-CA1 synapses in living behaving mice and monitored spontaneous neuronal firing and network formation in primary neuronal cultures of Prnp(ZH3/ZH3) vs wildtype mice. PrP(C) absence enhanced susceptibility to high-intensity stimulations and kainate-induced seizures. However, long-term potentiation (LTP) was not enhanced in the Prnp(ZH3/ZH3) hippocampus. In addition, we observed a delay in neuronal maturation and network formation in Prnp(ZH3/ZH3) cultures. Conclusion Our results demonstrate that PrP(C) promotes neuronal network formation and connectivity. PrP(C) mediates synaptic function and protects the synapse from excitotoxic insults. Its deletion may underlie an epileptogenic-susceptible brain that fails to perform highly cognitive-demanding tasks such as associative learning and anxiety-like behaviors.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/182571
url https://hdl.handle.net/2445/182571
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1186/s12915-021-01203-0
Bmc Biology, 2022, vol. 20, num. 1
https://doi.org/10.1186/s12915-021-01203-0
info:eu-repo/grantAgreement/EC/H2020/713140
dc.rights.none.fl_str_mv cc-by (c) Matamoros i Anglès, Andreu et al., 2022
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Matamoros i Anglès, Andreu et al., 2022
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 25 p.
application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv Articles publicats en revistes (Biomedicina)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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