Colleen and Garrett to present at Student Seminar Thursday (19.Nov) at noon in 2166 MERF
Colleen and Garrett will be presenting Student Seminar this week in 2166 MERF at noon. I have asked the speakers to provide a brief overview for their talks. Hope to see you there!
Background for Garrett’s talk
Since its initial discovery in 1949, lithium continues to be prescribed to patients suffering from bipolar affected disorder (BPD). However, the underlying mechanisms of how this drug elicits its mood-stabilizing effect remain unknown. To help identify these lithium-responsive processes, we have used the dominant, X-linked Drosophila mutant Shudderer (Shu). This mutant is characterized by strong jerking and twitching as well as uncoordinated locomotion. Interestingly, the severity of Shu phenotypes can be significantly reduced upon lithium administration(1). Our behavioral, anatomical and genetic investigations of this mutant have led to the following findings. Lithium improves Shu mutant climbing and reduces the severity of the jerking phenotypes. In contrast the same doses of lithium have no significant impact on the same behaviors in wild-type flies. Shu mutants exhibit down-turned wings and an indentation of the dorsal thorax, a phenotype previously observed in mutants with neuronal excitability. Classic meiotic mapping suggests that the Shu mutation lies near chromosomal region 14D-15F. Microarray gene expression profiling of the Shu mutant revealed that CanA-14F, which encodes a catalytic subunit of the Ca2+/calmodulin-dependent Ser/Thr protein phosphatase calcineurin is up-regulated 2.2-fold compared to wild-type. To determine if a reduction in CanA-14F levels could improve the mutant phenotypes, hypomorphic mutant alleles of CanA-14F were introduced into the Shu background. The resultant flies transheterozygous for Shu and the CanA-14F hypomorphic alleles showed a reduction in morphological defects as well as a significant improvement in behavior. Lastly, expression of the endogenous inhibitor of calcineurin activity, nebula (nla) was sufficient to suppress the morphological phenotypes in Shu when driven in neurons. Rescue was not observed when expressed in glia, muscle or fat bodies. These data suggest that overexpression of CanA-14F, and a subsequent increase in calcineurin activity in the nervous system play a role in the manifestation of the Shu phenotypes.
Recent evidence in two human association studies has shown the calcineurin A subunit gene PPP3CC to be a risk factor in both schizophrenia and BPD (2, 3). Furthermore, several calcineurin mutant mouse models show behavioral deficits reminiscent of those observed in schizophrenia and other mental disorders (4, 5).
1. R. L. Williamson, Psychopharmacology (Berl) 76, 265 (1982).
2. F. Mathieu et al., Behav Brain Funct 4, 2 (2008).
3. D. J. Gerber et al., Proc Natl Acad Sci U S A 100, 8993 (Jul 22, 2003).
4. T. Miyakawa et al., Proc Natl Acad Sci U S A 100, 8987 (Jul 22, 2003).
5. C. J. Herzog, S. Miot, I. M. Mansuy, B. Giros, E. T. Tzavara, Eur J Pharmacol 580, 153 (Feb 2, 2008).