Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis

Abstract

The molecular pathogenesis of bipolar disorder (BPD) is poorly understood. Using human-induced pluripotent stem cells (hiPSCs) to unravel such mechanisms in polygenic diseases is generally challenging. However, hiPSCs from BPD patients responsive to lithium offered unique opportunities to discern lithium's target and hence gain molecular insight into BPD. By profiling the proteomics of BDP-hiPSCderived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). Active nonphosphorylated CRMP2, which binds cytoskeleton, is present throughout the neuron; inactive phosphorylated CRMP2, which dissociates from cytoskeleton, exits dendritic spines. CRMP2 elimination yields aberrant dendritogenesis with diminished spine density and lost lithium responsiveness (LiR). The "set-point" for the ratio of pCRMP2:CRMP2 is elevated uniquely in hiPSC-derived neurons from LiR BPD patients, but not with other psychiatric (including lithium-nonresponsive BPD) and neurological disorders. Lithium (and other pathway modulators) lowers pCRMP2, increasing spine area and density. Human BPD brains show similarly elevated ratios and diminished spine densities; lithium therapy normalizes the ratios and spines. Consistent with such "spine-opathies," human LiR BPD neurons with abnormal ratios evince abnormally steep slopes for calcium flux; lithium normalizes both. Behaviorally, transgenic mice that reproduce lithium's postulated site-of-action in dephosphorylating CRMP2 emulate LiR in BPD. These data suggest that the "lithium response pathway" in BPD governs CRMP2's phosphorylation, which regulates cytoskeletal organization, particularly in spines, modulating neural networks. Aberrations in the posttranslational regulation of this developmentally critical molecule may underlie LiR BPD pathogenesis. Instructively, examining the proteomic profile in hiPSCs of a functional agent-even one whose mechanism-of-action is unknownmight reveal otherwise inscrutable intracellular pathogenic pathways. have proven valuable for studying the molecular pathology of monogenic diseases, one of the technique's greatest challenges has been to offer similar insights into the molecular pathogenesis of polygenic, multifactorial disorders for which the underlying pathophysiology is unknown. The struggle has been to go beyond phenotypic description to discerning underlying molecular mechanisms. Neuropsychiatric illnesses are a prototype for such complex conditions (1-3). They are difficult to model not only because of the likelihood of polygenic influences, but also because of the subjectivity with which these diseases must often be diagnosed, the empirical fashion with which drugs are prescribed, and the heterogeneity of patient response. Of such maladies, bipolar disorder

Higher in vivo Cortical Intracellular Volume Fraction Associated with Lithium Therapy in Bipolar Disorder: A Multicenter NODDI Study

“…Hence, findings reporting modifications of the grey matter compartment associated with lithium in humans and in preclinical studies have been replicated [2-4, 25, 26]. However, the cellular changes involved in grey matter plasticity remain unknown.…”

CRMP 2 mediates Sema3F‐dependent axon pruning and dendritic spine remodeling

“…This suggests that even a minor difference in the spatio-temporal inactivation of CRMP2 during development can have a major impact on the development and severity of the resulting neurodevelopmental defects. In the full CRMP2 knockout mice, we generated, we found several phenotypical defects present in the published conditional and full CRMP2 knockout mice (e.g., ventriculomegaly, spine density changes in DG, working memory defects, or hyperactivity) [17,73]. We also found brain sizes comparable in both WTs and crmp2 À/À mice, similar as reported in the CRMP2 knockout mice [17,73], although we detected a non-significant tendency for a thinner cortex in the knockout mice (not shown) in agreement with the hypoplastic corpus callosum and anterior commissure.…”

Lacosamide in bipolar disorder: A 30‐day comparison to a retrospective control group treated with other antiepileptics

“…Lacosamide stabilizes the slow‐inactivated state of neuronal Na v 1.1 and Na v 1.7 channels, but was shown also to act on Na v 1.2, Na v 1.3, and Na v 1.8, but not on Na v 1.6, whose gene SCN8A was found to be possibly associated with BD . One possible connection with lacosamide‐influenced processes is indirect, stemming from the fact that lithium, an effective antimanic agent, normalizes the pCRMP2‐to‐CRMP2 ratio and restores aberrant neuronal spine densities in human‐induced pluripotent stem cells from lithium‐responsive BD patients . CRMP2, which is known to regulate responses to Na v 1.7 channels is a target of lacosamide, but how much this is relevant to its action in BD is still to establish.…”