Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder

Mertens, Jérôme; Wang, Qiu-Wen; Kim, Yongsung; Yu, Diana; Pham, Son; Yang, Bo; Zheng, Yi; Diffenderfer, Kenneth E.; Zhang, Jian; Soltani, Sheila; Eames, Tameji; Schäfer, Simon; Boyer, Leah; Marchetto, Maria C.; Nürnberger, John I.; Calabrese, Joseph R.; Oedegaard, Ketil J.; McCarthy, Michael J.; Zandi, Peter P.; Alda, Martin; Nievergelt, Caroline M.; Mi, Shuangli; Brennand, Kristen J.; Kelsoe, John R.; Gage, Fred H.; Yao, Jun

doi:10.1038/nature15526

Cited by 506 publications

(563 citation statements)

References 29 publications

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“…69,70 The relatively modest improvement of b-wave amplitude by lithium was potentially negated by its direct suppressive effects on neuronal synaptic transmission, which is the primary rationale of its use to treat bipolar disease and mental disorders. 71 Although the incidence of FEVR is rare, the impact of vision impairment on the life quality of patients with severe FEVR is quite high, especially because they may experience vision impairment very early in life. 72 Patients with FEVR usually have a family history and hence may be diagnosed early, yet intervention options remain quite limited.…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy

Wang

Liu

Sun

et al. 2016

The American Journal of Pathology

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Section: Discussionmentioning

confidence: 99%

Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy

Wang

Liu

Sun

et al. 2016

The American Journal of Pathology

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“…S12. ) channel blockers have proved clinically ineffective as a monotherapy for this condition (13), speaking against hyperexcitability as the primary target of LiR (2). Although previous studies looked at the total number of firings of populations of neurons over a given period (2), we sought to analyze Ca i 2+ flux in individual LiR BPD neurons (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The struggle has been to go beyond phenotypic description to discerning underlying molecular mechanisms. Neuropsychiatric illnesses are a prototype for such complex conditions (1)(2)(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.…”

mentioning

confidence: 99%

“…The former, however, could lend insight into the latter. For example, although lithium may suppress hyperexcitability of a subset of neurons in culture (2) [many mechanisms have been proffered (4)], clinical trials have shown that drugs that simply suppress neuronal activity, such as calcium channel blockers, are ineffective in BPD (7). Furthermore, of the one-third of patients who are LiR, many become noncompliant because of frequent adverse side effects (e.g., weight gain, hypothyroidism, tremor, kidney dysfunction, dermatologic reactions, teratogenicity).…”

mentioning

confidence: 99%

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

Tobe

Crain

Winquist

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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136

121

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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

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“…The recent evidence that neurons derived from BD patients showed hyper-excitability and increased expression of neurotransmission-related genes (Mertens et al, 2015) led us to investigate potential transcriptional similarities between the gene expression profile of Tph2 mutants and that of BD neurons. Notably, Gene Set Enrichment Analysis (GSEA) (Subramanian et al, 2005) showed statistically significant enrichment of the KO mouse transcriptional signature as compared to that of BD neurons.…”

mentioning

confidence: 99%

Serotonin buffers hippocampal neuroplasticity and emotional behavior

Maddaloni

Migliarini

Napolitano

et al. 2017

Preprint

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Adaptation to environmental insults is an evolutionary mechanism essential for survival. The hippocampus participates in controlling adaptive responses to stress and emotional state through the modulation of neuroplasticity events, which are dysregulated in stress-related neuropsychiatric disorders. The neurotransmitter serotonin (5-HT) has been proposed as a pivotal player in hippocampal neuroplasticity in both normal and neuropsychiatric conditions though its role remains still poorly understood. Here, we investigated the impact of 5-HT deficiency on hippocampal activity combining RNA-seq, in vivo neuroimaging, neuroanatomical, biochemical and behavioral experiments on 5-HT depleted mice. We unveil that serotonin is required for appropriate activation of neuroplasticity adaptive mechanisms to environmental insults. Bidirectional deregulation of these programs in serotonin depleted mice is associated with opposite behavioral traits that model core symptoms of bipolar disorder. These findings delineate a previously unreported buffering role of 5-HT in instructing hippocampal activity and emotional responses to environmental demands.

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Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder

Cited by 506 publications

References 29 publications

Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy

Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy

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

Serotonin buffers hippocampal neuroplasticity and emotional behavior

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