1. Intracellular Signalling Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower St, London WC1E 6BT, UK
2. Cellular Neurobiology Group, Department of Biology, University College London, Gower St, London WC1E 6BT, UK
3. These authors contributed equally to this work

Correspondence to: Anne W. Mudge^2,3 Correspondence and requests for materials should be addressed to A.W.M. (e-mail: Email: a.mudge@ucl.ac.uk).

Abstract

Lithium, carbamazepine and valproic acid are effective mood-stabilizing treatments for bipolar affective disorder. The molecular mechanisms underlying the actions of these drugs and the illness itself are unknown. Berridge and colleagues¹ suggested that inositol depletion may be the way that lithium works in bipolar affective disorder, but others have suggested that glycogen synthase kinase^{2, 3} (GSK3) may be the relevant target. The action of valproic acid has been linked to both inositol depletion^{4, 5} and to inhibition of histone deacetylase⁶ (HDAC). We show here that all three drugs inhibit the collapse of sensory neuron growth cones and increase growth cone area. These effects do not depend on GSK3 or HDAC inhibition. Inositol, however, reverses the effects of the drugs on growth cones, thus implicating inositol depletion in their action. Moreover, the development of Dictyostelium is sensitive to lithium⁷ and to valproic acid, but resistance to both is conferred by deletion of the gene that codes for prolyl oligopeptidase, which also regulates inositol metabolism. Inhibitors of prolyl oligopeptidase reverse the effects of all three drugs on sensory neuron growth cone area and collapse. These results suggest a molecular basis for both bipolar affective disorder and its treatment.