Fig. 5. Schematic representation of our reverse translational findings in mice and patients.

Reverse translational findings reveal that exosomal mitophagy alterations are linked to oxidative stress-induced impairments of parvalbumin interneuron (PVI)-microcircuit in association with gamma oscillation alterations and cognitive deficit. In prefrontal cortex and in blood of redox dysregulated mice (Gclm-KO + GBR), oxidative stress induces miR-137 upregulation, leading to decreased COX6A2 and mitophagy markers, including NIX, Fundc1 and LC3B, and to accumulation of damaged mitochondria. This would further exacerbate oxidative stress and PVI impairments in a positive feedforward process. MitoQ, a mitochondria-targeted antioxidant, rescued all these processes. Translating to early psychosis patients, blood exosomal miR-137 increases and COX6A2 decreases, combined with mitophagy markers alterations suggest that observations made centrally and peripherally in the animal model were reflected in patients’ blood. Higher exosomal miR-137 and lower COX6A2 levels were also associated with a reduction of ASSR gamma oscillations in EEG. As ASSR requires proper PVI-related networks, alterations in combined miR-137/COX6A2 plasma exosome levels may represent a proxy marker of PVI cortical microcircuit impairment that are critically involved in SZ psychopathology and cognition. Blue line: positive correlations; red line: negative correlations; black dashed line: loss/gain association.