PrPC Controls via Protein Kinase A the Direction of Synaptic Plasticity in the Immature Hippocampus

The cellular form of prion protein PrP C is highly expressed in the brain, where it can be converted into its abnormally folded isoform PrP Sc to cause neurodegenerative diseases. Its predominant synaptic localization suggests a crucial role in synaptic signaling. Interestingly, PrP C is developmentally regulated and its high expression in the immature brain could be instrumental in regulating neurogenesis and cell proliferation. Here, PrP C -deficient ( Prnp 0/0 ) mice were used to assess whether the prion protein is involved in synaptic plasticity processes in the neonatal hippocampus. To this aim, calcium transients associated with giant depolarizing potentials, a hallmark of developmental networks, were transiently paired with mossy fiber activation in such a way that the two events were coincident. While this procedure caused long-term potentiation (LTP) in wild-type (WT) animals, it caused long-term depression (LTD) in Prnp 0/0 mice. Induction of LTP was postsynaptic and required the activation of cAMP-dependent protein kinase A (PKA) signaling. The induction of LTD was presynaptic and relied on G-protein-coupled GluK1 receptor and protein lipase C. In addition, at emerging CA3-CA1 synapses in WT mice, but not in Prnp 0/0 mice, pairing Schaffer collateral stimulation with depolarization of CA1 principal cells induced LTP, known to be PKA dependent. Postsynaptic infusion of a constitutively active isoform of PKA catalytic subunit Cα into CA1 and CA3 principal cells in the hippocampus of Prnp 0/0 mice caused a persistent synaptic facilitation that was occluded by subsequent pairing. These data suggest that PrP C plays a crucial role in regulating via PKA synaptic plasticity in the developing hippocampus.