Abstract Background The cellular prion protein (PrP C ) has been associated with numerous cellular processes, such as cell differentiation and neurotransmission. Moreover, it was recently demonstrated that some functions were misattributed to PrP C since results were obtained from mouse models with genetic artifacts. Here we elucidate the role of PrP C in the hippocampal circuitry and its related functions, like learning and memory, using the new strictly co-isogenic Prnp 0/0 mouse (Prnp ZH3/ZH3 ) . Behavioral and operant conditioning tests were performed to evaluate memory and learning capabilities. In vivo electrophysiological recordings were carried out at CA3-CA1 synapses in living behaving mice, and spontaneous neuronal firing and network formation were monitored in primary neuronal cultures of Prnp ZH3/ZH3 vs . wild-type mice. Results Results showed decreased motility, impaired operant conditioning learning, and anxiety-related behavior in Prnp ZH3/ZH3 animals. 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 In conclusion, PrP C mediates synaptic function and protects the synapse from excitotoxic insults. Its deletion might evoke a susceptible epileptogenic brain that would fail to perform highly cognitive-demanding tasks such as associative learning and anxiety-like behaviors.

Behavioral deficits, learning impairment, and enhanced hippocampal excitability in co-isogenic PrnpZH3/ZH3 mice