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Mitochondrial Dysfunction in Schizophrenia: Determination of Mitochondrial Respiratory Activity in a Two-Hit Mouse
Cécile Monpays1, Jessica Deslauriers1, Philippe Sarret1
1Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 12e avenue Nord, Sherbrooke, QC, J1H 5N4, Canada.
Abstract:
Schizophrenia is a chronic mental illness in which mitochondrial dysfunction has been suggested. Our laboratory recently developed a juvenile murine two-hit model (THM) of schizophrenia based on the combination of gestational inflammation, followed by juvenile restraint stress. We previously reported that relevant behaviors and neurochemical disturbances, including oxidative stress, were reversed by the antioxidant lipoic acid (LA), thereby pointing to the central role played by oxidative abnormalities and prompting us to investigate mitochondrial function. Mitochondrial activity was determined with the MitoXpress® commercial kit in two schizophrenia-relevant regions (prefrontal cortex (PFC) and striatum). Measurements were performed in state 3, with substrates for complex I- and complex II-induced respiratory activity (IRA). We observed an increase in complex I IRA in the PFC and striatum in both sexes but an increase in complex II activity only in males. LA treatment prevented this increase only in complex II IRA in males. Expression levels of the different respiratory chain complexes, as well as fission/fusion proteins and protein carbonylation, were unchanged. In conclusion, our juvenile schizophrenia THM shows an increase in mitochondrial activity reversed by LA, specifically in complex II IRA in males. Further investigations are required to determine the mechanisms of these modifications.
Insights
This study investigated mitochondrial function in a juvenile mouse model of schizophrenia. Lipoic acid (LA) reversed increased mitochondrial activity in males, suggesting a role for oxidative stress in this chronic mental illness.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Psychiatry
Background:
- Schizophrenia is a chronic mental illness linked to mitochondrial dysfunction.
- A juvenile two-hit model (THM) of schizophrenia was developed using gestational inflammation and juvenile restraint stress.
- Previous studies showed lipoic acid (LA) reversed behavioral and neurochemical disturbances in this model.
Purpose of the Study:
- To investigate mitochondrial function in a juvenile schizophrenia THM.
- To determine the effects of lipoic acid (LA) on mitochondrial activity in this model.
Main Methods:
- Mitochondrial activity was measured using the MitoXpress® kit in the prefrontal cortex (PFC) and striatum.
- Complex I- and Complex II-induced respiratory activity (IRA) were assessed in state 3.
- Expression levels of respiratory chain complexes and fission/fusion proteins were analyzed.
Main Results:
- Increased Complex I IRA was observed in the PFC and striatum of both sexes.
- Increased Complex II IRA was found only in males.
- LA treatment ameliorated the increase in Complex II IRA specifically in males.
- Expression levels of respiratory chain complexes, fission/fusion proteins, and protein carbonylation remained unchanged.
Conclusions:
- The juvenile schizophrenia THM exhibits altered mitochondrial activity, particularly Complex II IRA in males.
- Lipoic acid (LA) demonstrates a sex-specific reversal of mitochondrial dysfunction in this model.
- Further research is needed to elucidate the precise mechanisms underlying these mitochondrial modifications.
