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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.

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