The mood-stabilising drugs lithium and valproic acid (VPA) are used in the treatment of bipolar disorder, but the molecular mechanisms underlying their therapeutic effects are not well understood at present. Both drugs have been suggested to attenuate inositol-based signalling: Lithium by depleting the intracellular pool of inositol via uncompetitive inhibition of Inositol monophosphatase (IMPase) and Inositol polyphosphate-1-phosphatase (IPPase), and VPA by inhibition of inositol de novo synthesis. The therapeutic time courses for lithium and VPA treatment suggest that the drugs exert their effects through changing gene expression. Therefore, the aim of the present study was to test the hypothesis that lithium sensitivity in the model system Dictyostelium discoideum (D.discoideum) is caused by changes in gene expression. Real-time PCR and motility assays were used to investigate whether (1) changes in gene expression can be observed in lithium-resistant mutants, (2) overexpression of IMPase and lno1 leads to lithium resistance, and (3) lithium and analogues of the bipolar drug VPA affect gene expression. I found that (1) loss of prolyl oligopeptidase (DpoA) in the lithium resistant LisA mutant or loss of a chromatin-remodelling factor (mutation remains to be confirmed) in the lithium resistant LisG mutant increased lno1 and IPP1 expression. (2) Overexpression of lno1 or IMPase led to resistance against lithium, and also VPA and the VPA-analogue VGD. (3) Lithium and VPA- analogues caused distinct changes in gene expression: Lithium treatment increased the expression of enzymes involved in inositol phosphate signalling, with the exception of IMPase VGD decreased the expression of IMPase, IPP1 and dpoA. In addition, the LisG mutant, which showed increased IPP1 expression, was found to be cross-resistant to VGD. The present study shows that lithium sensitivity in D.discoideum correlates with changes in gene expression and suggests that increase in lno1 and IPP1 expression may confer lithium resistance in D.discoideum.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:436340 |
| Date | January 2006 |
| Creators | Keim-Reder, Melanie |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1445630/ |
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