Di Daniel, E.; (2007) Mechanisms of action of mood-stabilizing drugs. Doctoral thesis , University of London.

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Abstract

Bipolar disorder or manic-depression is a severe and common psychiatric illness that is often treated with mood-stabilizing drugs. Several molecular targets and signalling pathways have been implicated in the pathophysiology of the illness and in the mechanism of action of these drugs. However, the precise targets that are responsible for the therapeutic action and side-effects of the drugs are not known. In this PhD thesis we have analysed some of the potential drug targets, in particular extracellular signal-regulated kinase mitogen-activated protein kinase (ERK/MAPK) and glycogen synthase kinase-3 (GSK.3). which mood stabilizers are believed to regulate. We showed, using cell and biochemical assays, that the effects of lithium, valproate or carbamazepine on ERIC MAPK are not always observed in a given cell type. In addition, only lithium inhibits GSK3 directly and modulation of this kinase with potent and selective inhibitors does not mimic the effects of mood stabilizers on cortical and sensory neuron growth cone morphology. A major part of my thesis focused on the enzyme prolyl oligopeptidase (PO), which is thought to modulate the phosphatidylinositol pathway, as shown from studies in Dictyostelium discoideum and human astroglioma cells. PO inhibitors alone have no effect on sensory neuron growth cone morphology, but reverse the growth cone changes induced by mood stabilizers, mimicking addition of/m-o-inositol to the culture media. We studied PO null-mutant mice and analysed the effects of mood stabilizers on the morphology of growth cones from these mice. Unexpectedly, the PO null-mutant phenotype itself resembled wild-type neurons treated with a mood stabilizer and each drug had no further effect on growth cone morphology. These results show that PO is a critical component of signalling pathways involved in mood-stabilizing drug action on growth cones. Using viral delivery of native or catalytically-dead PO, we showed that each restored the wild-type phenotype. In order to better understand PO function, a yeast-tvvo-hybrid screen (Y2H) was also performed at Gla.xoSmithK.line to determine protein interactors for PO, and we analysed one of these interactors, namely GAP43. We showed that both the native and the catalytically-dead PO co-precipitate with the neuronal protein GAP43. These results show that there are additional biological effects of PO independent of its catalytic domain.

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