Mitochondrial, exosomal miR137-COX6A2 and gamma synchrony as biomarkers of parvalbumin interneurons, psychopathology, and neurocognition in schizophrenia

Ines Khadimallah,Chrysa Retsa,Kim Q Do,Martine Cleusix,Michel Cuenod,Raoul Jenni,Kevin M Spencer,Philippe Conus,Margot Fournier,Jan-Harry Cabungcal,Milena Siciliano,Micah M Murray,Elidie Beard,Jean-François Knebel,Paul Klauser,Pascal Steullet

doi:10.1038/s41380-021-01313-9

Abstract

Early detection and intervention in schizophrenia requires mechanism-based biomarkers that capture neural circuitry dysfunction, allowing better patient stratification, monitoring of disease progression and treatment. In prefrontal cortex and blood of redox dysregulated mice (Gclm-KO ± GBR), oxidative stress induces miR-137 upregulation, leading to decreased COX6A2 and mitophagy markers (NIX, Fundc1, and LC3B) and to accumulation of damaged mitochondria, further exacerbating oxidative stress and parvalbumin interneurons (PVI) impairment. MitoQ, a mitochondria-targeted antioxidant, rescued all these processes. Translating to early psychosis patients (EPP), blood exosomal miR-137 increases and COX6A2 decreases, combined with mitophagy markers alterations, suggest that observations made centrally and peripherally in animal model were reflected in patients’ blood. Higher exosomal miR-137 and lower COX6A2 levels were associated with a reduction of ASSR gamma oscillations in EEG. As ASSR requires proper PVI-related networks, alterations in miR-137/COX6A2 plasma exosome levels may represent a proxy marker of PVI cortical microcircuit impairment. EPP can be stratified in two subgroups: (a) a patients’ group with mitochondrial dysfunction “Psy-D”, having high miR-137 and low COX6A2 levels in exosomes, and (b) a “Psy-ND” subgroup with no/low mitochondrial impairment, including patients having miR-137 and COX6A2 levels in the range of controls. Psy-D patients exhibited more impaired ASSR responses in association with worse psychopathological status, neurocognitive performance, and global and social functioning, suggesting that impairment of PVI mitochondria leads to more severe disease profiles. This stratification would allow, with high selectivity and specificity, the selection of patients for treatments targeting brain mitochondria dysregulation and capture the clinical and functional efficacy of future clinical trials.

Highlights

Among the most perdurable observations in schizophrenia (SZ) is a functional impairment of cortical parvalbumin interneurons (PVIs) [1]
Recent research points to OxS as one “central hub” in SZ pathophysiology, with converging evidence from environmental and genetic studies linking this process to PVI impairment [6]: in series of animal models carrying either genetic and/or environmental risks, we showed that PVI deficits were all accompanied by oxidative stress in prefrontal cortex
MitoQ treatment rescues oxidative stress-induced miR-137, COX6A2, mitophagy, and PVI alterations In view of the detrimental effects of OxS on PVI integrity, miR-137 expression level, COX6A2 protein level, and mitophagy, we evaluated whether treatment with MitoQ, a selective mitochondria-targeted antioxidant [41], could rescue these deficits in young KO mice

Summary

Introduction

Among the most perdurable observations in schizophrenia (SZ) is a functional impairment of cortical parvalbumin interneurons (PVIs) [1]. Association between miR-137 and COX6A2 exosomal levels with auditory steady-state responses (ASSR) in early psychosis patients As an increase in miR-137 level is associated with PVIs in Gclm-KO mice, based on the hypotheses that the ASSR reflects PVI integrity [48] and that increased plasma miR-137 levels in the EPP group represent a proxy marker of PVI impairment, we tested whether high plasma miR-137 levels could be associated with ASSR deficits.

Results

Conclusion