American Association of Neuropathologists, Inc. Abstracts of the 91st Annual Meeting June 11–14, 2015 Denver, CO

Abstract

Mitochondrial dysfunction has been increasingly linked to neurodevelopmental disorders such as intellectual disability, childhood epilepsy and autism spectrum disorder; conditions also associated with cortical GABAergic interneuron dysfunction. Although interneurons have some of the highest metabolic demands in the postnatal brain, the importance of mitochondria during interneuron development is unknown. Remarkably, we find that the migration of interneurons is exquisitely sensitive to perturbations in oxidative phosphorylation. Both pharmacologic and genetic inhibition of Adenine Nucleotide Transferase 1 (Ant1) preferentially disrupts the non-radial, long-distance migration of interneurons from the basal forebrain to the cortex, thus reducing the numbers of cortical interneurons. These results provide a novel mechanism for the pathogenesis of neurocognitive disorders associated with mitochondrial dysfunction or other causes of oxidative stress, and suggest a common mechanistic pathway upon which multiple developmental and metabolic perturbations may converge.