BDK Deficiency in Cerebral Cortex Neurons Causes Neurological Abnormalities and Affects Endurance Capacity.

Branched-chain amino acid (BCAA) catabolism is regulated by its rate-limiting enzyme, branched-chain α-keto acid dehydrogenase (BCKDH), which is negatively regulated by BCKDH kinase (BDK). Loss of BDK function in mice and humans leads to dysregulated BCAA catabolism accompanied by neurological symptoms such as autism; however, which tissues or cell types are responsible for the phenotype has not been determined. Since BDK is highly expressed in neurons compared to astrocytes, we hypothesized that neurons are the cell type responsible for determining the neurological features of BDK deficiency. To test this hypothesis, we generated mice in which BDK deletion is restricted to neurons of the cerebral cortex (BDK ^Emx1-KO mice). Although BDK ^Emx1-KO mice were born and grew up normally, they showed clasped hind limbs when held by the tail and lower brain BCAA concentrations compared to control mice. Furthermore, these mice showed a marked increase in endurance capacity after training compared to control mice. We conclude that BDK in neurons of the cerebral cortex is essential for maintaining normal neurological functions in mice, and that accelerated BCAA catabolism in that region may enhance performance in running endurance following training.