CHARACTERIZATION OF DIACYLGLYCEROL KINASES ETA AND IOTA IN ITCH, PAIN, AND PSYCHOPATHOLOGICAL BEHAVIOR IN MICE Public Deposited

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  • March 19, 2019
Creator
  • Bartsch, Victoria
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • Diacylglycerol kinases (DGK) control diverse signaling functions. Expression of the iota and eta isoforms of DGK (Dgki and Dgkh, respectively) are enriched in mouse neuronal tissues. By overexpressing Dgki and Dgkh in HEK293 cells, we found that Dgki and Dgkh enhanced G-protein-coupled receptor signaling and phosphorylated diacylglycerol and monoacylglycerol. We acquired a Dgki¬-knockout mouse and generated a Dgkh-knockout mouse and a double Dgki/Dgkh knockout (dKO) mouse. Using the Dgki-/-, Dgkh-/-, and dKO mice, we elucidated the role of Dgki and Dgkh in regulating behaviors associated with the neuronal tissues in which they are expressed. Dgki and Dgkh are highly expressed in small-diameter dorsal root ganglia (DRG) neurons, which detect pruritogenic (itch-causing) and algogenic (pain-causing) stimuli. We found that in vivo sensitivity to histamine—but not other pruritogens—was enhanced in male and female Dgki-/- mice, but was attenuated in Dgkh-/- males. Interestingly, dKO mice phenocopied the histamine sensitivity of the Dgki-/- mice. In contrast, baseline pain sensitivity and pain sensitization post-injury were equivalent between wild type (WT) and Dgki-/-, Dgkh-/-, or dKO mice. Even though diacylglycerol and monoacylglycerol kinase activity was reduced in DRGs from Dgkh-/- and dKO mice, in vitro signaling induced by pruritogens and algogens in DRG neurons was unaffected by Dgki or Dgkh deletion. Genome-wide association studies linked DGKH and DGKI to mood disorders, and both genes are expressed throughout the brain. dKO mice—but not Dgki-/- or Dgkh-/- mice—showed behavioral signs of anxiety and mania. Dgki-/- and dKO males showed hyperactivity and hyperexploratory behavior, as well. In addition to the psychopathological phenotypes, dKO females demonstrated deficits in maternal care. Fewer than 30% of newborn pups raised by dKO females survived to weaning; however, 85% of pups born from dKO dams survived when fostered by WT dams. Pups raised by dKO dams had smaller milk spots and reduced weight, indicative of impaired nursing. Together, our research suggests that Dgki and Dgkh regulate behavioral responses to histamine, without affecting responses to other pruritogens or algogens, and that combined deletion of Dgkh and Dgki disrupts mood-disorder-related phenotypes and impairs maternal behavior in the early postpartum period.
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  • In Copyright
Advisor
  • Otey, Carol
  • Nicholas, Robert
  • Tarran, Robert
  • Zylka, Mark
  • Nackley, Andrea
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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