Mitochondria Dysfunction Seen to Affect Interneuron Development in Brains of Mice, Possibly Leading to Neurological Disorders

Mitochondria Dysfunction Seen to Affect Interneuron Development in Brains of Mice, Possibly Leading to Neurological Disorders

Mitochondria dysfunction disrupts normal development of interneurons, which may underlie the neurological symptoms of autism spectrum disorder, according to the results of a recent study, “Differential Mitochondrial Requirements for Radially and Non-radially Migrating Cortical Neurons: Implications for Mitochondrial Disorders,” published in the journal Cell Reports.

Mitochondria are key organelles within cells responsible for generating the energy that cells need to work. Mitochondria dysfunction-associated diseases are among the most common inherited metabolic disorders.

Increasingly recognized is the link between mitochondrial dysfunction and neurodevelopmental disorders, such as intellectual disability, childhood epilepsy, and autism spectrum disorder. However, how mitochondria dysfunction leads to neurological problems is far from understood.

A team of researchers at the Brigham and Women’s Hospital (BWH) tackled this question, focusing specifically on the development of interneurons, key players responsible for creating neural circuits that allow communication between motor and sensory neurons and the central nervous system. Neurodevelopmental disorders have been reported to be associated with interneuron dysfunction.

Interneurons are capable of migrating and travel for long distances during the brain’s development. The researchers hypothesized that this migratory feature would require more energy (as compared to other types of neurons), so that mitochondria could have a determinant role.

The team found that interneuron migration from the basal forebrain to the neocortex is dependent on functional mitochondria, being especially sensitive to perturbations in oxidative phosphorylation — specifically, the pharmacological inhibition of key components of oxidative phosphorylation impaired normal interneurons migration.

To corroborate the pharmacological findings, researchers performed genetic assays by removing the adenine nucleotide transferase 1 (Ant1) gene, which is critical for maintaining a correct mitochondrial oxidative phosphorylation. They observed that mice lacking Ant1 displayed dramatic alterations in interneurons migratory morphology and behavior. This phenotype was specific to interneurons, as projection neurons showed no alterations in their migratory path.

In conclusion, results showed that a healthy mitochondrial function is essential for the prenatal development of a critical cerebral cortical neuronal subpopulation. Furthermore, the study suggested that neurological disorders, such as autism spectrum disorder and intellectual disability, may arise not only as a result of energetic deficits but also due to abnormal interneuron development.

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