Prions induce an early Arc response in the hippocampus of prion-infected mice

Synapse dysfunction and synaptic loss are a central feature of neurodegenerative disorders, including prion disease. The cellular prion protein (PrPC) binds prion, amyloid-β, tau, and α-synuclein oligomers, resulting in the activation of macromolecular complexes and signaling at the post-synapse, yet the initial signaling events are unclear. Here we used a transcriptomic approach focused on the early-stage, prion-infected hippocampus of male wild type mice, and identify immediate early genes, including the synaptic activity response gene, Arc/Arg3.1, as significantly upregulated. In a longitudinal study of the prion-infected hippocampus, Arc/Arg-3.1 protein increased, from early to terminal disease. Notably, metabotropic glutamate receptor levels (mGluR5 dimers) were markedly reduced over time, while phosphorylated AMPA receptors (pGluA1-S845) levels increased. Sporadic Creutzfeldt-Jakob disease (sCJD) post-mortem cortical samples also showed low levels of mGluR5 dimers. Together, these findings suggest that prions trigger a chronic Arc response, an increase in phosphorylated GluA1, and a reduction in mGluR5 receptors beginning in early disease. RNA-seq for prion (22L strain)- or mock-inoculated C57/BL6J male mice at 63 days post inoculation or 40% in disease progression to terminal disease