Synaptic proteomics as a means to identify the molecular basis of mental illness: Are we getting there?

Synapses are centrally involved in many brain disorders, particularly in psychiatric and neurodevelopmental ones. However, our current understanding of the proteomic alterations affecting synaptic performance in the majority of mental illnesses is limited. As a result, novel pharmacotherapies with improved neurological efficacy have been scarce over the past decades. The main goal of synaptic proteomics in the context of mental illnesses is to identify dysregulated molecular mechanisms underlying these conditions. Here we reviewed and performed a meta-analysis of previous neuroproteomic research to identify proteins that may be consistently dysregulated in one or several mental disorders. Notably, we found very few proteins reproducibly altered among independent experiments for any given condition or between conditions, indicating that we are still far from identifying key pathophysiological mechanisms of mental illness. We suggest that future research in the field will require higher levels of standardization and larger-scale experiments to address the challenge posed by biological and methodological variability. We strongly believe that more resources should be placed in this field as the need to identify the molecular roots of mental illnesses is highly pressing.