Our hypothesis was that if UPR activation, known to be associated with synaptic failure and neuronal demise, leads to dysregulation of a specific set of proteins, then UPR-targeted treatments should, at least in part, reverse this.

We found that the decline in protein synthesis during disease reflects, in particular, the significant reduction in many proteins critical for synaptic and mitochondrial function, with an increase in apoptosis signalling in neurons. Critically, these changes are reversed by trazodone treatment, which remarkably largely restores the entire diseased-brain nascent proteomes both in the bulk hippocampal tissue and cell-specifically in hippocampal neurons and astrocytes. In parallel, trazodone treatment had both structural and functional protective effects on synapses and mito-chondria, consistent with the changes specific to protein synthesis, restoring reduced numbers of both mitochondria and synapses, and restoring impaired mitochondrial function essential for synap-tic and neuronal health.