Abstract
For over fifty years the elemental cation lithium (Li⁺) has been the primary agent used in the treatment and prophylaxis of bipolar disorder, but its therapeutic mechanism of action remains unknown. Bipolar disorder is associated with alterations in ion distributions and may be the result of abnormal ion channel function. Consistent with this, anticonvulsants which block voltage gated sodium (Na⁺) channels are the second most commonly prescribed mood stabilisers, after Li⁺, for the treatment of bipolar disorder. How Li+ may share a membrane effect with the anticonvulsants has presented an unresolved paradox. While anticonvulsants block voltage gated Na⁺ channels, Li⁺ readily enters neurons through voltage gated Na⁺ channels and can replace Na⁺ in membrane depolarisation. This paradox has deterred the development of an ion channel hypothesis for the mechanism of action of the anticonvulsants and Li⁺ in the treatment of bipolar disorder, and may have prevented progress in understanding of the pathophysiology of this disease.
Recent work has indicated that voltage gated Na⁺ channels are functionally and structurally coupled to potassium (K⁺) channels sensitive to the intracellular concentration of Na⁺, these channels generate the Na+ activated K+ conductance (IKNa⁺). Evidence suggests that Li+ cannot replace Na⁺ in IKNa⁺ channel activation, however, because previous studies investigating IKNa⁺ channels have replaced the majority of external Na⁺ with Li⁺, the effect of low concentrations of Li⁺ on IKNa⁺ channels in the presence of physiologically relevant Na⁺ levels is unclear. If lower, more therapeutically relevant concentrations of Li⁺ were to interfere with IKNa⁺ channel activation this would suggest a common target of Li⁺ and the anticonvulsants on the electrical membrane properties of brain neurons. Li⁺ may directly block IKNa⁺ channels, and the anticonvulsants indirectly block IKNa⁺ channels through their primary effect to block voltage gated Na⁺ channels.
The work in this thesis has provided a systematic characterisation of the effects of low concentrations of Li⁺ on the electrical properties of a neuronal membrane. The results indicate that Li⁺ increases membrane excitability, and decreases the decay slope and after-hyperpolarisation (AHP) of individual action potentials, consistent with decreased activation of IKNa⁺ channels. Li⁺ is shown to decrease the activation of a persistent, voltage dependent outward current active at subthreshold potentials, an effect dependent upon Li⁺ entry into neurons through voltage gated Na+ channels. These effects of Li⁺ cannot be explained by a simple inability of Li⁺ to activate IKNa⁺ current, and it is proposed that low concentrations of Li⁺ actively interferes with Na+ activation of IKNa⁺ channels.
This work indicates that Li⁺ has a direct effect on the electrical properties of neurons. Interestingly, anticonvulsant drugs, also used in the treatment of bipolar disorder, have long been known to alter the electrical properties of neurons through inhibition of voltage gated Na⁺ channels. Based on our findings with Li⁺ and the well characterised effects of the anticonvulsants, we propose that Li+ and the anticonvulsants target structurally and functionally coupled ion channels involved in the short and long term control of membrane excitability. This is consistent with increasing genetic evidence indicating that bipolar disorder could be a disease of ion channels (a channelopathy), and has exciting implications for our understanding of the pathophysiology of mood disorders.