Reduced phosphatases and hyperphosphorylated glutamatergic receptors persist from early to late stages of prion disease

Synapse loss occurs early in prion disease, yet the intracellular signaling driving this dysregulation remains poorly understood. Evidence of neuronal hyperactivity was reported in humans with sporadic and familial CJD as well as in the early stages of prion disease in mice (strain 22L). Here we perform a longitudinal study of prion-infected mice (strain RML) and show an increase in the immediate-early gene, Arc, suggesting this is a conserved response to prions. We also observed a persistent decrease in phosphatase abundance (PP1 and PP2B) starting at the earliest timepoint (preclinical) in the cerebral cortex. At this stage, mGluR5 dimers and phosphorylated AMPA receptors were increased. By clinical disease onset, mGluR5 dimers declined, and activity shifted toward NMDA receptor activation, marked by GluN2B hyperphosphorylation. Together, these findings suggest that early phosphatase reduction accompanies neuronal hyperactivity and precedes substantial inflammation. Elucidating the mechanisms driving this early phosphatase loss and its role in neuronal hyperactivity may reveal novel therapeutic targets for prion disease.