The lack of cellular prion protein might lead to epilepsy symptoms and learning deficits

Researchers at IBEC, in collaboration with hospitals and international partners, have observed that the deficiency of the cellular prion protein leads to behavioral deficits, learning impairment, and enhanced epilepsy-like excitability of the brain, in mice.

Cellular prion protein (PrPC), a molecule located on the surface of neural cells, is known for being imbalanced in human patients suffering neurodegenerative diseases such as Alzheimer’s or Parkinson´s disease. However, increasing knowledge about the participation of PrPC in these diseases contrasts with data regarding its natural and health-promoting role. This means that while in some studies this protein has been described as protective for the brain, in other studies PrPC expression was associated with increased susceptibility to neurotoxicity.

Such inconsistences are mainly due to the absence of an appropriate and well characterized mice models. To bring some light to the real role of PrPC on neural physiology, researchers at the Institute for Bioengineering of Catalonia (IBEC), led by José Antonio del Río, full Professor of the University of Barcelona and group leader of IBEC have been intensively working in the last five years on new transgenic mice lacking PrPC generated using the TALEN technology, and they report now surprising results at BCM Biology Journal. 

Scientists from Molecular and Cellular Neurobiotechnology IBEC´s Group, in collaboration with the University Hospital of Zürich, University of Barcelona and the Pablo de Olavide University in Seville (Spain), have found that absence of PrPC impairs cognitive functions such as associative learning and memory, and producing anxiety-like behavior. Experts also found that the deficiency of PrPC leads to an increased susceptibility to epilepsy seizures in these mice. 

Researchers have been working for decades with PrPC modified mice, without knowing the impact on their health due that previously developed models presented some technical pitfalls. Using a TALEN generated PrPC knock-out mice, we have found now that the animals that does not express the protein present epileptic-like symptoms and impaired learning and memory which reinforce the role of the protein in these processes and might help to understand the effects of their decrease observed in some neurodegenerative diseases in humans. 

José Antonio del Río, Group Leader at IBEC 

In their study, researchers performed a full set of behavioral and operant conditioning tests to evaluate memory and learning capabilities of mice, in parallel with RNAseq, in vitro neuron network analysis and in vivo electrophysiological data. The results showed a clear decreased motility, impaired operant conditioning learning, and anxiety-related behavior in the animals lacking PrPC.  

Results demonstrate that PrPC protein promotes neuronal network formation and connectivity, and mediates synaptic function, also protecting from excitotoxic. Deletion of PrPC may underlie an epileptogenic-susceptible brain that fails to perform highly cognitive-demanding tasks such as associative learning and anxiety-like behaviors. 

This study developed last years was supported by La Caixa Research, by PRPSEM Project from Spanish Ministry of Science and Innovation, by CIBERNED, the CERCA Programme, and the Commission for Universities and Research of the Department of Innovation, Universities, and Enterprise of the Generalitat de Catalunya. 

Reference article: Matamoros-Angles et al. Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability. BMC Biology 2022.