Ndufs4 KO mice: A model to study comorbid mood disorders associated with mitochondrial dysfunction

Area of Science:

• Neuroscience
• Mitochondrial Biology
• Psychiatry

Background:

• Mitochondrial diseases, like Leigh syndrome, are linked to psychiatric comorbidities.
• Major depression and bipolar disorder involve mitochondrial dysfunction.
• The Ndufs4 knockout (KO) mouse is a model for mitochondrial complex I dysfunction.

Purpose of the Study:

• To investigate the neuropsychiatric profile of Ndufs4 KO mice.
• To link behavioral alterations with brain biomarkers in Ndufs4 KO mice.
• To explore the translational relevance of Ndufs4 KO mice for mood disorders.

Main Methods:

• Behavioral screening of Ndufs4 KO, heterozygous (HET), and wildtype (WT) mice (postnatal days 28-35).
• Assessed locomotor activity, depressive-like, and anxiety-like behaviors.
• Analyzed serotonin, kynurenine, and redox status (GSH/GSSG) in brain regions (prefrontal cortex, hippocampus, striatum).

Main Results:

• Ndufs4 KO mice exhibited depressive-like behavior (tail suspension test) but not consistently (forced swim test).
• Increased risk resilience was observed in the mirror box test.
• Elevated serotonin, altered tryptophan/kynurenine turnover, decreased kynurenine/kynurenic acid turnover, and increased GSH/GSSG ratio were found in KO mice.

Conclusions:

• Ndufs4 KO mice display a neuropsychiatric profile relevant to mitochondrial disorders.
• The behavioral profile of Ndufs4 KO mice resembles rodent models of bipolar disorder, including variable mood and risk-taking.
• This model may help elucidate bio-energetic mechanisms in mood disorders associated with mitochondrial disease.