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

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.

Neuronal Cultures: Exploring Biophysics, Complex Systems, and Medicine in a Dish

“…Altogether, our partnership with medical teams provided answers to difficult humanlevel explorations or preliminary results for future human therapies. Our compromise is strong and, in addition to Parkinson's disease and the above physicochemical actions, we have contributed to advance biomedical questions in Sanfilippo [30], Huntington's disease [25,26,31], Alzheimer's disease [14], and cellular prion pathogenesis [32]. From left to right, data correspond to a healthy culture, a culture derived from cells affected by a genetic form of PD, and a culture whose cells were genetically-edited to correct for the disease.The PD culture exhibits an excessive integration, with stronger synchronization in the raster plots and bigger communities; (b) recovery of an aggregated culture after laser microsurgery (yellow spot before damage, black spots after it).…”

“…In partnership with different research institutes in medicine, we have helped investigating the goodness of cell therapies, e.g., gene editing or transplantation, as well as the potential use of new chemical compounds as pharmacological agents. See Refs [14,20,[25][26][27][28][29][30][31][32]…”

Cell type-specific translatome analysis of mouse models of three genetic neurodegenerative diseases

“…In contrast to Huntingtin, Prnp null mutants are viable and a variety of Prnp knock-out models have been generated [58][59][60] . However, these mice show diverse phenotypic variations, which has led to a variety unrelated of roles being attributed to PrP c , including involvement in phagocytosis of apoptotic cells 61 , involvement in synaptic function 62,63 , and myelin homeostatsis 64 . It was later found that several of these effects may instead originate from genes flanking the Prnp locus and co-segregating with Prnp.…”

Extracellular vesicles with diagnostic and therapeutic potential for prion diseases

“…Most recently, the N-terminal copper-binding site of PrP C was demonstrated to be essential for neuronal protection and neuritogenesis (Nguyen et al 2019 ). In addition, to overcome the issue with genetic artefacts associated to lack of proper PrP C knockout models in several of the PrP C functions indicated above, a more physiologically relevant co-isogenic Prnp 0/0 mouse model ( Prnp ZH3/ZH3 ) was developed (Matamoros-Angles et al 2022 ; Nuvolone et al 2016 ). The co-isogenic PrP C knockout model studies demonstrated a vital role in peripheral myelin maintenance, neural network formations, synaptic regulations and cognitive abilities (Matamoros-Angles et al 2022 ; Nuvolone et al 2016 ).…”

“…In addition, to overcome the issue with genetic artefacts associated to lack of proper PrP C knockout models in several of the PrP C functions indicated above, a more physiologically relevant co-isogenic Prnp 0/0 mouse model ( Prnp ZH3/ZH3 ) was developed (Matamoros-Angles et al 2022 ; Nuvolone et al 2016 ). The co-isogenic PrP C knockout model studies demonstrated a vital role in peripheral myelin maintenance, neural network formations, synaptic regulations and cognitive abilities (Matamoros-Angles et al 2022 ; Nuvolone et al 2016 ). Thus, multiple functions of PrP C suggest that the abnormal conformation due to conversion into PrP TSE generates potential disturbances in various biological processes leading to pathogenesis in PrD.…”