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

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.

Caught in vicious circles: a perspective on dynamic feed-forward loops driving oxidative stress in schizophrenia

“…By adopting the reverse translation of validated circuitryrelevant human endpoints approach [2], we provide convincing proof-of-concept for targeting OxS through antioxidant-based strategies in individuals with schizophrenia and underscore the importance of "breaking" the various vicious circles associated with OxS as means to prevent the propagation of processes that may precede the onset of disease. To improve early detection and increase the signal-to-noise ratio for adjunctive trials of antioxidants, anti-inflammatory and NMDAR modulator drugs, the above presented processes allow to identify mechanismbased biomarkers guiding stratification of homogenous patients groups and target engagement required for successful clinical trials, paving the way towards precision medicine in psychiatry [90,116,143,209,212]. Presently, it is not easy to interfere with the genetic component of the disease nor fully prevent the impact of environmental factors.…”

“…Sulforaphane works through the NRF2 system to trigger the anti-oxidant defence system [222]. b MitoQ and other mitochondria-targeted antioxidants could support compromised energy metabolism and mitochondria function [116]. c For NMDAR hypofunction, several strategies using compounds (e.g., D-serine, sarcosine, glycine transporter inhibitor and benzoate) that modulate NMDAR activity have been tried in schizophrenia patients with mixed success [217,[223][224][225][226][227][228][229].…”

“…Moreover, higher exosomal miR-137 and lower COX6A2 levels were associated with weaker EEG 40-Hz auditory steady-state response. As auditory steady-state response requires proper PV neuron-related networks [116], these suggest that alterations of combined miR-137/COX6A2 plasmatic exosomal levels represent a proxy marker of impairments of cortical PV neuron microcircuits. These findings allowed to stratify early psychosis patients in two subgroups: (a) patients "with mitochondrial dysfunction" characterized by exosomal high miR-137 and low COX6A2, presumably representing PV neuron dysfunction associated with mitochondria and (b) patients "without mitochondrial dysfunction" having miR-137 and COX6A2 levels within the healthy control range.…”

“…In PFC of Gclm KO mice, we identified a novel molecular mechanism linking mitochondria and OxS-induced PV neuron impairments. OxS induces upregulation of the microRNA miR-137 in PV neurons, leading to decreased COX6A2, a subunit of cytochrome c oxidase complex IV specific to PV neurons, and to impaired mitophagy with accumulation of damaged mitochondria [116]. Remarkably, the mitochondria-targeted antioxidant, mitoquinone mesylate (MitoQ), rescues this entire pathological process.…”

Is There a Glutathione Centered Redox Dysregulation Subtype of Schizophrenia?

“…Finally, a third factor such as altered resting-state cerebral blood flow may lead to mitochondrial dysfunction, leading to both an increase in free radical species followed by lowered GSH and concomitant glutamatergic deficit. Recent evidence supports the notion of impaired mitochondrial function (especially, mitophagy, the elimination of defective mitochondria) in schizophrenia [ 140 ], though its relationship with GSH and glutamate in schizophrenia requires further investigation.…”