TARGETING THE MITOCHONDRIAL QUALITY CONTROL IN MODELS OF NEURODEVELOPMENTAL DISORDERS BASED ON BRAIN-ENVIRONMENT INTERACTION

Schizophrenia is a severe, chronic, neurodevelopmental disorder with genetic association with mitochondrial dysfunction. This study explores the mitochondrial quality control using two mouse models of neurodevelopmental disorders i.e., the adult offspring of dams either exposed to restraint stress (PRS) or injected with methylazoxymethanol (MAM) during pregnancy. PRS, MAM and the respective controls mice were treated daily for 20 days with vehicle or with pyrroloquinoline quinone (PQQ, 20 mg/kg) in combination with either omaveloxolone (OMV, 10 mg/kg) or dimethyl fumarate (DMF, 10 mg/kg), two drugs that are known to enhance mitochondrial biogenesis. We evaluated mice behaviour using the open field, and the novel object recognition and social interaction tests. Protein of mitochondrial respiratory complexes and mitochondrial quality control (mitophagy, fusion, fission and biogenesis) were evaluated in the prefrontal cortex (PFC) and hippocampus (HP) using western blot analysis. In male MAM mice we found an increase in complex I/IV proteins and nuclear respiratory factor-1 (NRF1) in the PFC and HP, and a decrease in PGC-1α (an activator of mitochondrial biogenesis) in the PFC. In addition, Rab5 and Rab7 (mitophagy) protein levels were decreased in both regions of male and female MAM mice, respectively. Changes in mitochondrial regulatory proteins of PRS mice are under evaluation. Behavioural analysis of PRS mice showed an increased locomotory activity and decreased social interaction, which improved after treatment with PQQ+OMV in both sexes, and with PQQ+DMF only in female mice.These initial findings suggest that changes in mitochondrial function and mitochondrial quality control occur in models of neurodevelopmental disorders.