Circulating vesicular mirna derived from neurons are associated with cognitive impairment and treatment resistance in individuals with schizophrenia

The molecular composition of neurons is specific to the functional state and is altered during disease. While these alterations may be detected in postmortem analyses, the ethical constraints, small sample sizes and other confounders are insurmountable for well-powered population studies and biomarker development. Given that neurons release extracellular vesicles (EVs) which reflect their origin, we hypothesized that the fractionation of neuron derived EVs provides an opportunity to specifically profile their encapsulated contents non-invasively from blood. To explore this possibility, we determined miRNA expression MAP1B-enriched serum EVs derived from neurons from a large cohort of individuals with schizophrenia or no history of psychiatric illness. Aliquots of serum from the Australian Schizophrenia Research Bank (ASRB) cohort (n=477) were incubated with MAP1B antibody-coupled magnetic beads to capture neuronal origin extracellular vesicles. Total RNA was extracted for small RNA library preparation and sequenced. Differential expression based on diagnostic and cognitive criteria was performed using edgeR, adjusting for batch, sex and age. Dysregulation of miRNA was observed in individuals with schizophrenia and included brain enriched molecules such as hsa-miR-92a-3p and has-miR-486-5p, with demonstrated roles in synaptic plasticity and corticogenesis. Importantly, individuals with severe disease (cognitive impairments and treatment resistance) showed greater alterations than those observed in non-severe disease counterparts. Overall, there was a trend for increased vesicular expression of miRNA in schizophrenia subjects, suggesting the cell of origin hosts an abundance of regulatory molecules. Predicted target genes of miRNA differentially expressed in schizophrenia are enriched for neuronal, synaptic and neurotransmitter annotations. Additionally, miRNA targets were also enriched with genes genetically associated with schizophrenia. We observed profound dysregulation of brain expressed miRNA in cognitive deficit and treatment resistant schizophrenia in serum EVs from neural origin. Many of the altered miRNA identified in the current work have previously been found to be dysregulated in schizophrenia from analyses of CNS tissues, suggesting our non-invasive method can detect disease related molecules. The individual miRNA, the transcripts they target and genetic association with schizophrenia suggest functional consequences for adult neurogenesis and synaptic neuropathology.