National Academy of Sciences, Proceedings of the National Academy of Sciences, 22(114), 2017
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Significance One-third of bipolar disorder (BPD) patients are lithium-responsive (LiR) for unknown reasons. Were lithium’s target to be identified, then BPD’s pathogenesis might be unraveled. We identified and mapped the “lithium-response pathway,” which governs the phosphorylation of CRMP2 , a cytoskeleton regulator, particularly for dendritic spines: hence, a neural network modulator. Although “toggling” between inactive (phosphorylated) and active (nonphosphorylated) CRMP2 is physiologic, the “set-point” in LiR BPD is abnormal. Lithium (and other pathway-modulators) normalize that set-point. Hence, BPD is a disorder not of a gene but of the posttranslational regulation of a developmentally critical molecule. Such knowledge should enable better mechanistically based treatments and bioassays. Instructively, lithium was our “molecular can-opener” for “prying” intracellularly to reveal otherwise inscrutable pathophysiology in this complex polygenic disorder.