Targeting the Cellular Prion Protein for Synaptic Function and Network Dynamics

The cellular prion protein (PrP^C) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein, primarily known for its involvement in the pathogenesis of prion diseases. Its biological functions remain only partially understood. Recent research implicates PrP^C in neuronal development, excitability, and synaptic plasticity, as well as in other biological processes. Here, we investigate its role on different developmental stages, both in vitro and in vivo, using different PrP knock-out (KO) mouse lines (Prnp^0/0).

The electrophysiological properties of neuronal networks derived from wild-type and Prnp^0/0 mice were characterized using microelectrode arrays (MEAs). KO neurons displayed altered network dynamics, including a reduced frequency of population bursts and less synchronous activity, indicative of impaired maturation of the synaptic circuitry. These functional alterations were associated with a reduced expression of key presynaptic and postsynaptic proteins, including elements of the SNARE complex and regulators of excitation-inhibition balance.

The molecular data could be replicated in a second Prnp^0/0 model, suggesting that PrP^C is directly involved in these mechanisms regardless of genetic backgrounds. 

Furthermore, alterations in neuronal networks were also identified in vivo in adult Prnp^0/0 mice, including increased neuronal responses to visual danger stimuli, which correlated with behaviorally increased fear responses to those stimuli. 

Together, our findings support a critical role for PrP^C in the establishment and maintenance of functional neuronal networks, from early developmental stages in vitro to behaviorally mature relevant circuits in vivo, beyond genomic background. These results indicate that PrP^C acts as a key regulator of synaptic development and function, influencing both physiology and pathology.