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

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• dc.contributor.author Matamoros-Angles, Andreu
• dc.contributor.author Hervera, Arnau
• dc.contributor.author Soriano, Jordi
• dc.contributor.author Martí, Eugènia
• dc.contributor.author Carulla, Patricia
• dc.contributor.author Llorens, Franc
• dc.contributor.author Nuvolone, Mario
• dc.contributor.author Aguzzi, Adriano
• dc.contributor.author Ferrer, Isidre
• dc.contributor.author Gruart, Agnès
• dc.contributor.author Delgado García, José María
• dc.contributor.author del Río, José Antonio
• dc.date.accessioned 2022-03-28T06:31:24Z
• dc.date.available 2022-03-28T06:31:24Z
• dc.date.issued 2022
• dc.description.abstract Background: Cellular prion protein (PrPC) 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 PrPC in prion pathogenesis contrasts with puzzling data regarding its natural physiological role. PrPC 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 PrPC, with some functions recently shown to be misattributed to PrPC due to the presence of genetic artifacts in mouse models. Here we elucidate the role of PrPC in the hippocampal circuitry and its related functions, such as learning and memory, using a recently available strictly co-isogenic Prnp0/0 mouse model (PrnpZH3/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 PrnpZH3/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 PrnpZH3/ZH3 vs wildtype mice. PrPC absence enhanced susceptibility to high-intensity stimulations and kainate-induced seizures. However, long-term potentiation (LTP) was not enhanced in the PrnpZH3/ZH3 hippocampus. In addition, we observed a delay in neuronal maturation and network formation in PrnpZH3/ZH3 cultures. Conclusion: Our results demonstrate that PrPC promotes neuronal network formation and connectivity. PrPC 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.
• dc.description.sponsorship This research was supported by PRPSEM Project with ref. RTI2018-099773-B-I00 from MCINN/AEI/10.13039/501100011033/ FEDER “Una manera de hacer Europa”, the CERCA Programme, and the Commission for Universities and Research of the Department of Innovation, Universities, and Enterprise of the Generalitat de Catalunya (SGR2017-648), CIBERNED (CMED2018-2) to JADR and IF. The project leading to these results received funding from the “la Caixa” Foundation (ID 100010434) under the agreement LCF/PR/HR19/52160007 and the María de Maeztu Unit of Excellence (Institute of Neurosciences, University of Barcelona) MDM-2017-0729 to JADR. JS was supported by FIS2016-78507-C2-2-P from (MCIU/FEDER/AEI), SGR2017-1061 from the Generalitat de Catalunya, and the European Union’s Horizon 2020 research and innovation program under the grant agreement No. 713140 (MESOBRAIN). Support was also received from MINECO (BFU2017-82375-R), and Junta de Andalucía (BIO-122, UPO-1250734, and P18-FR-823) grants to AG and JMDG. F.LL. was supported by Instituto Carlos III (grant PI19-00144). A.M-A. was supported by the Tatiana Pérez de Guzmán el Bueno Foundation.
• dc.format.mimetype application/pdf
• dc.identifier.citation Matamoros-Angles A, Hervera A, Soriano J, Martí E, Carulla P, Llorens F. et al. Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability. BMC Biol. 2022 Jan 13;20(1):17. DOI: 10.1186/s12915-021-01203-0
• dc.identifier.doi http://dx.doi.org/10.1186/s12915-021-01203-0
• dc.identifier.issn 1741-7007
• dc.identifier.uri http://hdl.handle.net/10230/52780
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof BMC Biol. 2022 Jan 13;20(1):17
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/713140
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/FIS2016-78507-C2-2-P
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-82375-R
• dc.rights © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Anxiety
• dc.subject.keyword Behavior
• dc.subject.keyword Cellular prion protein
• dc.subject.keyword Epilepsy
• dc.subject.keyword Hippocampus
• dc.subject.keyword LTP
• dc.title Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion