changes in zebrafish anesthetic sensitivity in response to the loss of are associated with the alteration of mitochondrial motility.

Anesthetic and sedative drugs are small compounds known to bind to hundreds of proteins. One intriguing binding partner of propofol is the kinesin motor domain, kif5A, a neuronal mitochondrial transport protein. Here, we used zebrafish WT and KO larval behavioral assays to assess anesthetic sensitivity and combined that with zebrafish primary neuronal cell culture to probe for alteration in mitochondrial motility. We found that the loss of increases behavioral sensitivity to propofol and etomidate, with etomidate hypersensitivity greater than propofol. In contrast, KO animals were resistant to the behavioral effects of dexmedetomidine. Finally, WT and KO larvae responded similarly to the behavioral effects of ketamine. Propofol inhibited the anterograde motility of mitochondria in WT zebrafish neurons, while etomidate inhibited mitochondrial motility in both anterograde and retrograde directions; neither drug altered mitochondrial motility in the knockout (KO) neurons. In contrast, dexmedetomidine enhanced retrograde mitochondrial motility in both WT and KO animals. Finally, ketamine had little significant effect on mitochondrial motility in either mutant or WT animals. These data demonstrate that each anesthetic/sedative drug affects the motor protein machinery uniquely and is associated with unique changes in behavior. Understanding how different anesthetic compounds alter neuron motor proteins will be important in defining how anesthetics alter neuronal signaling and energetic dynamics.