PKR downregulation prevents copper-induced synaptic dysfunction in a murine model of Wilson’s disease

Abstract

Abstract Synaptic efficacy is critical for memory formation and consolidation. Accumulating evidence suggest that synapses are impaired during Wilson’s disease (WD), contributing to neuronal dysfunction and cognitive decline. However, the mechanisms mediating the inhibitory synaptic dysfunction in WD are not fully understood. We investigated the effects of the PKR/eIF2α pathway on the synaptic structure and function of neurons in WD using a murine model (TX mice). During open-field tests for the mice, we observed significant decreases in immobility time and time spent in the center, accompanied by an increase in escape latency in the WD model animals, suggesting that chronic copper deposition leads to cognitive dysfunction. We also found a decrease in the expression of synapse-associated proteins (Synapsin1, Synaptophysin, PSD93, PSD95, and VAMP2) as well as abnormal neurotransmitter levels (including glutamate and GABA), indicating the presence of synaptic dysfunction in the TX mice. Inhibiting PKR via C16 prevented these changes, suggesting that dysfunctional cognition is associated with the PKR/eIF2α pathway. We also observed changes in synapses, vesicles, dendritic spine density, and dendritic length associated with the presence of cognitive dysfunction. Further investigation revealed that C16 treatment decreased the TUNEL-positive cell numbers in the hippocampus of TX mice, and prevented 8-OHdG-induced synaptic dysfunction in the WD model mice. Our results suggest that PKR downregulation prevents copper-induced synaptic dysfunction in the murine WD model. Therefore, targeting PKR pharmacologically may be a potential therapeutic strategy for treating the copper-induced neuropathology of patients with WD.