Synaptic dysfunction is the main cause of memory-associated cognitive deficits in neurodegenerative disease and is a prequel to neuronal demise.65,66 Our data show that during prion disease, when synapse loss is established but neuronal loss is imminent—10 wpi in tg37+/− mice and 18 wpi in NCAT mice—that levels of predominantly neuronal synaptic proteins, both presynaptic (including SYN2, STX1B, SYNGR1, SYP) and postsynaptic (including SYNGAP1, DLG4, SLC6A11) are lowered by disease but restored by trazodone treatment (Fig. 3 and Supplementary Table 2). This evidence concerns the gene DLG4 and neurodegenerative disease.