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2022-01-13

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cc-by (c) Matamoros i Anglès, Andreu et al., 2022
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/182571

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

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https://doi.org/10.1186/s12915-021-01203-0

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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.

Matèries

Glicoproteïnes, Hipocamp (Cervell)

Matèries (anglès)

Glycoproteins, Hippocampus (Brain)

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Articles publicats en revistes (Biomedicina)
<b>Publicacions de projectes de recerca finançats per la UE</b>
Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))
Articles publicats en revistes (Institut de Neurociències (UBNeuro))
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Citació

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. Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability. _Bmc Biology_. 2022. Vol. 20, núm. 1. [consulta: 23 de gener de 2026]. ISSN: 1741-7007. [Disponible a: https://hdl.handle.net/2445/182571]

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