Temporary alteration of neuronal network communication is a protective response to redox imbalance that requires GPI-anchored prion protein

Abstract

Cellular prion protein (PrP^C) protects neurons against oxidative stress damage. This role is lost upon its misfolding into insoluble prions in prion diseases, and correlated with cytoskeletal breakdown and neurophysiological deficits. Here we used mouse neuronal models to assess how PrP^C protects the neuronal cytoskeleton, and its role in network communication, from oxidative stress damage. Oxidative stress was induced extrinsically by potassium superoxide (KO₂) or intrinsically by Mito-Paraquat (MtPQ), targeting the mitochondria. In mouse neural lineage cells, KO₂ was damaging to the cytoskeleton, with cells lacking PrP^C (PrP^-/-) damaged more than wild-type (WT) cells. In hippocampal slices, KO₂ acutely inhibited neuronal communication in WT controls without damaging the cytoskeleton. This inhibition was not observed in PrP^-/- slices. Neuronal communication and the cytoskeleton of PrP^-/- slices became progressively disrupted and degenerated post-recovery, whereas the dysfunction in WT slices recovered in 5 days. This suggests that the acute inhibition of neuronal activity in WT slices in response to KO₂ was a neuroprotective role of PrP^C, which PrP^-/- slices lacked. Heterozygous expression of PrP^C was sufficient for this neuroprotection. Further, hippocampal slices from mice expressing PrP^C without its GPI anchor (PrP^GPI-/-) displayed acute inhibition of neuronal activity by KO₂. However, they failed to restore normal activity and cytoskeletal formation post-recovery. This suggests that PrP^C facilitates the depressive response to KO₂ and its GPI anchoring is required to restore KO₂-induced damages. Immuno spin-trapping showed increased radicals formed on the filamentous actin of PrP^-/- and PrP^GPI-/- slices, but not WT and PrP^+/- slices, post-recovery suggesting ongoing dysregulation of redox balance in the slices lacking GPI-anchored PrP^C. The MtPQ treatment of hippocampal slices temporarily inhibited neuronal communication independent of PrP^C expression. Overall, GPI-anchored PrP^C alters synapses and neurotransmission to protect and repair the neuronal cytoskeleton, and neuronal communication, from extrinsically induced oxidative stress damages.

Keywords: Hippocampal CA1 long-term potentiation; Neuronal cytoskeleton; Neuronal network communication; Oxidative stress; PrP; Prion disease; Prion protein; Synaptic transmission.