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J Neurosci. 2013 Feb 13;33(7):2973-83. doi: 10.1523/JNEUROSCI.4149-12.2013.

PrPC controls via protein kinase A the direction of synaptic plasticity in the immature hippocampus.

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  • 1Scuola Internazionale Superiore di Studi Avanzati, 34136 Trieste, Italy.

Abstract

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.

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