Developmental Stage-Dependent Changes in Mitochondrial Function in the Brain of Offspring Following Prenatal Maternal...

Area of Science:

• Neuroscience
• Developmental Biology
• Toxicology

Background:

• Maternal immune activation (MIA) is a significant risk factor for neurodevelopmental disorders, including autism spectrum disorder (ASD).
• Understanding the specific mechanisms linking MIA to neurodevelopmental deficits is crucial for identifying therapeutic targets.

Purpose of the Study:

• To investigate the developmental trajectory of mitochondrial dysfunction and oxidative stress in offspring following MIA.
• To determine if MIA-induced changes in mitochondrial function contribute to autism-like behavioral deficits.

Main Methods:

• Maternal immune activation was induced in pregnant rats via lipopolysaccharide administration at gestation day 9.5.
• Mitochondrial function, oxidative stress parameters (ROS, NADPH oxidase activity), ATP levels, and mitochondrial membrane potential were assessed in fetuses, 7-day-old pups, and adolescent offspring.
• Electron transport chain complex expression was analyzed in adolescent offspring.

Main Results:

• MIA increased NADPH oxidase activity and ROS production in fetuses and young pups.
• Mitochondrial membrane potential and ATP levels were reduced in fetuses and young pups.
• Adolescent offspring exhibited persistent ROS elevation, mitochondrial depolarization, reduced ATP generation, and downregulated electron transport chain complexes.
• ROS origins shifted from NADPH oxidase in infancy to damaged mitochondria in adolescence.

Conclusions:

• MIA induces early-stage oxidative stress and mitochondrial alterations in offspring.
• Persistent mitochondrial dysfunction and oxidative stress in adolescence suggest a critical role in the development of autism-like deficits.
• A vicious cycle of mitochondrial damage, ROS production, oxidative stress, and neuroinflammation may underlie MIA-associated neurodevelopmental disorders.