The present address of Henrik Hansen, Senior Scientist, PhD, Gubra aps, Agern Allé 1, DK-2970 Hørsholm, Denmark.
Kv7 (KCNQ) channel openers normalize central 2-deoxyglucose uptake in a mouse model of mania and increase prefrontal cortical and hippocampal serine-9 phosphorylation levels of GSK3β
Article first published online: 14 MAR 2012
© 2012 Neurosearch A/S. Journal of Neurochemistry © 2012 International Society for Neurochemistry
Journal of Neurochemistry
Volume 121, Issue 3, pages 373–382, May 2012
How to Cite
Kristensen, L. V., Sandager-Nielsen, K. and Hansen, H. H. (2012), Kv7 (KCNQ) channel openers normalize central 2-deoxyglucose uptake in a mouse model of mania and increase prefrontal cortical and hippocampal serine-9 phosphorylation levels of GSK3β. Journal of Neurochemistry, 121: 373–382. doi: 10.1111/j.1471-4159.2012.07704.x
- Issue published online: 10 APR 2012
- Article first published online: 14 MAR 2012
- Accepted manuscript online: 22 FEB 2012 02:39PM EST
- Received January 6, 2012; revised manuscript received January 25, 2012; accepted February 15, 2012.
- bipolar disease;
- KCNQ channel;
J. Neurochem. (2012) 121, 373–382.
Several metabolic neuroimaging studies have indicated that bipolar patients with mania exhibit alterations in metabolic activity, suggesting that perturbations in corticolimbic function contribute to the functional deficits associated with the disease. Because pharmacological stimulation of Kv7 channel function has shown anti-manic like efficacy in the D-amphetamine and chlordiazepoxide (AMPH+CDP) induced hyperactivity mouse model of mania, we addressed whether this effect of Kv7 channels could be associated with changes in cerebral [14C]2-deoxyglucose (2-DG) uptake, a surrogate marker of brain metabolic activity. Acute administration of the Kv7 channel modulators, retigabine (pan Kv7.2-Kv7.5 channel opener) and ICA-27243 (Kv7.2/Kv7.3 channel-preferring opener) reduced 2-DG uptake in several mouse forebrain structures with a brain regional signature similar to the mood stabilizers, lithium and valproate. Combined administration of AMPH+CDP enhanced 2-DG uptake in the striatum, cortex and thalamus, and both retigabine and ICA-27243 fully prevented this stimulatory effect of AMPH+CDP. In addition, both Kv7 channel openers dose-dependently increased phospho-serine-9 levels of GSK3β in the prefrontal cortex and hippocampus, a common molecular mechanism shared by anti-manic drugs. In combination, these data emphasize the potential of Kv7 channel openers in the treatment of bipolar disorder, and suggest that heteromeric Kv7.2/Kv7.3 channels may present a novel anti-manic therapeutic target.