Intracellular pathways underlying the effects of lithium

This is a short overview focusing on the biochemical interactions underlying the protective effects of lithium at the neuronal level. These include lithium modulation of autophagy, growth factors, excitotoxicity, and a variety of mechanisms underlying cell death, neurogenesis, and neuronal differentiation. All these effects represent the result of a multifaceted pharmacology, which is becoming more and more complex. Nonetheless, when trying to dissect the various mechanisms of action of lithium, two primary targets emerge: glycogen synthase kinase 3beta and phosphatidylinositol phosphatase. The numerous lithium effects on biochemical systems are placed downstream of these two main mechanisms. At several steps, these mechanisms interconnect to each other, thus making it difficult to keep distinct the biochemical cascades promoted by lithium. In this way, it is not surprising that, despite being described as different phenomena at the behavioral level, molecular mechanisms underlying the effects of lithium on mood, motor activity, and sensitization overlap with those responsible for neuroprotection and neurorestoration. It is likely that the ancestral role of this ion as a modulator of cell survival, cell growth, movement, and mood is the consequence of a few molecular mechanisms operating in different neuronal networks, where a variety of cascade events take place. This review is an attempt to elucidate the primary effects of lithium to interconnect the simpler targets to the most complex pharmacological effects.