Fig. 7.

A working model of how mutation of dbt results in abnormal, accordion behavior. Similar to mammalian systems, we propose that wild-type zebrafish regulate metabolism of BCAAS via the BCKD complex. Many of these metabolic or molecular steps (black arrows) might occur in organs in the gut (such as the liver and intestine) but also the CNS. Amino acids (AA), such as glutamine, are transported across the blood-brain barrier and used to generate glutamate, GABA and other neurotransmitters (NT). These neurotransmitters are required for coordinated nervous system output to orchestrate swimming behavior. In que mutants, we propose that impaired BCKD function results in the accumulation of BCAA and α-keto acids. This yields reduced retention and metabolism, and reduced transport of other amino acids (white arrows) across the blood-brain barrier, yielding diminished neurotransmitter synthesis. The abnormal levels of neurotransmitters contribute to aberrant nervous system output and abnormal, accordion behavior. It is also possible that elevated concentrations of α-keto acids directly disrupt neural circuits to cause accordion behavior.