ABSTRACT
Valproic acid (VPA) provides a common treatment for both epilepsy and bipolar disorder; however, common cellular mechanisms relating to both disorders have yet to be proposed. Here, we explore the possibility of a diacylglycerol kinase (DGK) playing a role in regulating the effect of VPA relating to the treatment of both disorders, using the biomedical model Dictyostelium discoideum. DGK enzymes provide the first step in the phosphoinositide recycling pathway, implicated in seizure activity. They also regulate levels of diacylglycerol (DAG), thereby regulating the protein kinase C (PKC) activity that is linked to bipolar disorder-related signalling. Here, we show that ablation of the single Dictyostelium dgkA gene results in reduced sensitivity to the acute effects of VPA on cell behaviour. Loss of dgkA also provides reduced sensitivity to VPA in extended exposure during development. To differentiate a potential role for this DGKA-dependent mechanism in epilepsy and bipolar disorder treatment, we further show that the dgkA null mutant is resistant to the developmental effects of a range of structurally distinct branched medium-chain fatty acids with seizure control activity and to the bipolar disorder treatment lithium. Finally, we show that VPA, lithium and novel epilepsy treatments function through DAG regulation, and the presence of DGKA is necessary for compound-specific increases in DAG levels following treatment. Thus, these experiments suggest that, in Dictyostelium, loss of DGKA attenuates a common cellular effect of VPA relating to both epilepsy and bipolar disorder treatments, and that a range of new compounds with this effect should be investigated as alternative therapeutic agents.
This article has an associated First Person interview with the first author of the paper.
Footnotes
Competing interests
R.S.B.W. has a range of patents submitted regarding new treatments for epilepsy and bipolar disorder, including compounds cited in this study.
Author contributions
Conceptualization: C.J.W., R.S.B.W.; Methodology: E.K., D.S., R.S.B.W.; Validation: D.S.; Formal analysis: E.K., D.S., R.S.B.W.; Investigation: E.K., D.S., R.S.B.W.; Data curation: E.K., R.S.B.W.; Writing - original draft: E.K., R.S.B.W.; Writing - review & editing: E.K., D.S., C.J.W., R.S.B.W.; Visualization: E.K., R.S.B.W.; Supervision: C.J.W., R.S.B.W.; Project administration: C.J.W., R.S.B.W.; Funding acquisition: R.S.B.W.
Funding
This work was supported by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/L001500/1).
Supplementary information
Supplementary information available online at http://dmm.biologists.org/lookup/doi/10.1242/dmm.035600.supplemental
- Received May 10, 2018.
- Accepted July 3, 2018.
- © 2018. Published by The Company of Biologists Ltd
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.