Neural Control of Locomotor Behavior
Locomotive behavior relies upon the precise timing and coordination of muscle contractions on the left and right sides of the animal. These muscle contractions are coordinated by neural networks in the spinal cord. In previous studies we analyzed various zebrafish mutants that demonstrate a specific abnormal behavior, however when we began our studies the identity of the mutated gene was not known. These fish can be useful tools to better understand how genetic networks enable locomotion. Normal fish perform alternate muscle contractions on the left and right sides of the body to produce the alternating body bends that allow the animal to swim through the water. However, some mutant fish perform simultaneous muscle contractions on the left and right sides of the animal, that results in compression like an accordion. We and others have determined the molecular identity of the genes mutated in several lines of these fish, which encode proteins required for muscle relaxation, regulating neuromuscular synapses, and inhibition within the spinal cord. Surprisingly, one of these mutant fish contained disruptions in a gene required for the metabolism of certain amino acids (the building blocks of protein), which disrupted spinal cord function and swimming behavior. Humans that have mutations in the human version of this gene demonstrate a very similar inability to a degrade amino acids, which results Maple Syrup Urine Disease, a serious and poorly understood metabolic disorder. Our work established a zebrafish model of Maple Syrup Urine Disease.
Another line of mutant fish line demonstrate abnormal, hyperactive behavior caused by abnormal brainstem function. We found that this mutant, named ‘Techno Trousers’, has a reduced ability to clear the neurotransmitter glutamate from synapses, which causes elevated neuronal activity in the brainstem and spinal cord. We also found that blocking receptors for a different neurotransmitter, GABA, results in similar abnormal, hyperactive behavior. In current studies we are using a diverse array of approaches to further investigate how GABA receptors regulate locomotor networks to balance the activity of glutamate. Given that there are many similarities between the zebrafish and human brainstem, we expect our studies to have broad implications for human brainstem function.
Zebrafish as a Model For Epilepsy
The advantages that zebrafish offer for genetic and cellular analysis have also been used by several groups to study epilepsy. Epilepsy, the fourth most common neurological disease, consists of recurrent, spontaneous seizures. 70% of epilepsy cases can be treated, but not cured, with current medications. About 30% are uncontrollable with current drugs, which underscores the need to find new therapies. Interestingly, mutations in the human version of the gene mutated in the Techno Trousers fish described above cause a severe epilepsy syndrome. This finding, along with many other studies, show that abnormal zebrafish behavior can model seizures and epilepsy. A current project in the lab is focused on using genome editing to mutate the zebrafish versions of human genes that can cause genetic epilepsies. These zebrafish are being used to better understand how certain genes cause epilepsy and search for new genes that can suppress seizures. Given that larval zebrafish are tiny and aquatic, they are a great system for drug discovery. Eventually, we want to use zebrafish models of epilepsy as a high-throughput platform to identify novel anticonvulsant drugs.