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

A Matamoros-Angles,J Soriano,A Gruart,I Ferrer,M Nuvolone,F Llorens,J M Delgado-García,A Aguzzi,P Carulla,E Martí,J A Del Río,A Hervera

doi:10.1186/s12915-021-01203-0

Abstract

BackgroundCellular 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).ResultsWe 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.ConclusionOur 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.

Highlights

Cellular prion protein (PrPC) is a cell surface GPI-anchored protein, usually known for its role in the pathogenesis of human and animal prionopathies
In order to evaluate the implication of PrPC in systemic behavioral tasks, we took advantage of the new knock-out model, the PrnpZH3/ZH3 mouse
In contrast to Schmitz et al, where they used PrnpZH1/ZH1 mice, results showed a slightly increased but not significantly nest-building capacity in PrnpZH3/ZH3 compared to controls (PrnpZH3/ZH3 = 3.81 ± 0.64, n = 7 vs. Cellular prion protein gene (Prnp)+/+ = 3.00 ± 0.41, n = 7; mean ± S.E.M., p = 0.15; Mann-Whitney U non-parametric test) (Additional file 1: Fig. S1), suggesting that the two genotypes had similar welfare conditions [55]

Summary

Introduction

Cellular prion protein (PrPC) is a cell surface GPI-anchored protein, usually known for its role in the pathogenesis of human and animal prionopathies. 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. This controversy was strengthened by the absence, until a few years ago, of an appropriate Prnp0/0 mouse model without PrPC protein, with high breeding capability to dissect biological relevance in specific processes [9, 11,12,13]

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