Using human-induced pluripotent stem cells (hiPSCs) to unravel the molecular pathogenesis of complex, polygenic diseases has been challenging to the field. Viewing psychiatric conditions in general, and bipolar disorder (BPD) in particular, as prototypical for such inscrutable conditions, we developed a strategy to transform hiPSCs from being solely descriptive for such entities into a tool for revealing fundamental underlying molecular pathogenic mechanisms. One-third of BPD patients are lithium-responsive (LiR) for unknown reasons. Were lithium’s molecular target to be identified, we reasoned, then fundamental BPD’s pathogenesis might be unraveled. Through a combination of proteomic and bioinformatic pathway analyses of hiPSC-derived neurons from BPD patients followed by node-by-node mapping, animal modeling, intracellular imaging, functional validation in vitro and in vivo, and corroboration in human brains we recently published PNAS, 2017 that the “lithium-response pathway” in BPD governs the phosphorylation (hence, activity state) of “collapsin response mediator protein-2 (CRMP2)”, a “master” cytoskeleton regulator, particularly for dendrites and dendritic spines, hence, a neural network modulator.

Although “toggling” between inactive (phosphorylated) and active (non-phosphorylated) CRMP2 is physiologic, the “set-point” in LiR BPD is abnormal. Lithium (and other pathway-modulators) normalize that set-point (and, hence, spine morphology & function). Hence, BPD is a disorder not of a gene but of the post-translational regulation of a developmentally-critical molecule. Instructively, lithium was our “molecular can-opener” for “prying” intracellularly to reveal otherwise inscrutable pathophysiology in this complex polygenic disorder. Such knowledge has already begun to enable better mechanistically-based treatments and bioassays.

While providing the first functional molecular insight into BPD, it remained unclear how this aberration lead to the behavioral phenotype. To help address his question, we placed hiPSC-derived neurons into systems that map electrophysiological circuitry, intracellular calcium fluxes, and neurite proteomics. We learned that hyperkinetic neurons – counterintuitively – actually form impoverished neural networks with decreased complexity and signalling capacity (decreased network burst duration, frequency, firing rate). They also evince excessive “synchrony” (reminiscent of epilepsy) impairing pattern-mediated information transfer. In other words, BPD would appear to be a disorder more of “cognition” than of “mood”. Interestingly, these observations now provide a mechanistic understanding for the recent spate of large population genomic findings showing BPD to cluster with schizophrenia and autism rather than depression.

We have developed a “machine-learning classifier” trained on BPD neuronal calcium signaling which can diagnose BPD and predict lithium-responsiveness. It may also be useful in identifying and classifying cognitive disorders more broadly, including Alzheimer’s Disease and other cognitive disorders of aging, which may also be thought of as a cell non-autonomous “network’opathy” rooted, at least in part, in cytoskeletal dysregulation. In other words, we believe that, since hyper-excitable neurons characterize many neurodegenerative and traumatic CNS disorders (how one gets to that point obviously varies), and that hyper-excitable neurons make for hypo-functioning neural networks, a druggable target exists that could be broadly therapeutic in normalizing (via re-equilibration) some of the information processing dysfunctions that are common to many cognitive disorders, including those of aging and aging-related conditions.