In vivo changes in zebrafish anesthetic sensitivity in response to the loss of kif5Aa are associated with the alteration of mitochondrial motility

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Abstract
Anesthetic and sedative drugs are small compounds known to bind to hundreds of proteins. One intriguing binding partner of propofol is the motor domain of a neuronal mitochondrial transport kinesin, kif5A. Here, we used zebrafish wild type (WT) and kif5Aa knockout (KO) larval behavioral assays to assess anesthetic sensitivity and combined that with zebrafish primary neuronal cell culture to probe for alterations in mitochondrial motility. We found that the loss of kif5Aa increases behavioral sensitivity to propofol and etomidate, with etomidate hypersensitivity greater than propofol. In contrast, kif5Aa KO animals were resistant to the behavioral effects of dexmedetomidine. Finally, WT and kif5Aa 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 kif5Aa knockout (KO) neurons. In contrast, dexmedetomidine enhanced retrograde mitochondrial motility in both WT and kif5Aa 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.
Funding Information
  • Foundation for Anesthesiology Education and Research’s Mentored Research Training Grant
  • National Institute of General Medical Sciences (RM1 GM13651)
  • Center for Undergraduate Research and Fellowships at the University of Pennsylvania

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