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Psychiatric disorders

Modelling lithium responsiveness in a dish

Credit: Jennie Vallis/NPG

Induced pluripotent stem cell (iPSC) technology promises to enable the development of experimentally tractable and patient-specific cellular models of complex disorders. In their new study, Mertens et al. generated an iPSC-based model of bipolar disorder (BD), which revealed changes in the excitability of hippocampal neurons derived from patient iPSCs and shed light on the mechanisms through which lithium alleviates symptoms in a subset of patients.

To produce their model, the authors reprogrammed fibroblasts derived from six patients with manic type I BD and four controls. Hippocampal neuron number is known to be affected in individuals with BD, making it important to understand how the function of these cells is altered in the disorder. The authors therefore differentiated the iPSCs into hippocampal dentate gyrus granule cell-like neurons by incubating them with factors, including WNT-3A and brain-derived neurotrophic factor.

the BD neurons exhibited a hyperexcitable profile, including higher numbers of evoked APs and more-frequent spontaneous APs

RNA sequencing revealed several differences in the gene expression profile of 3-week-old BD and control iPSC-derived neurons, including changes in the expression of genes linked to mitochondrial function and neuronal excitability. The different gene expression profiles were mirrored by corresponding differences in neuronal function: the authors observed reduced mitochondrial size and enhanced function in BD neurons when compared to control neurons, and electrophysiological recordings revealed that the BD neurons exhibited a hyperexcitable profile, including higher numbers of evoked action potentials (APs) and more-frequent spontaneous APs.

Human patients with BD can be subdivided into a group in which treatment with lithium successfully relieves the symptom of mania and a group that is unresponsive to lithium. To determine whether this clinical phenomenon is replicated in the iPSC model, the authors examined the effects of 1-week incubation with lithium on the hyperexcitability of iPSC-derived neurons from patients with BD that are responsive to lithium (LR neurons) and those derived from patients that are unresponsive to lithium (NR neurons). Lithium reduced the hyperexcitability of LR neurons and partly normalized their mitochondrial function, whereas it had little effect on NR neurons. RNA sequencing revealed that lithium incubation also restored the levels of several genes (including some of those linked to abnormal mitochondrial function and AP firing) to control levels in LR neurons, whereas it had only a small effect on global gene expression in NR neurons.

As shown in this study, iPSC-based disease models may improve our understanding of the mechanisms underlying symptoms and differences in patient responsiveness to particular treatments. Such models may therefore lead to the development of new biomarkers and therapeutic targets to aid the treatment of complex psychiatric disorders.

References

  1. Mertens, J. et al. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 527, 95–99 (2015)

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Whalley, K. Modelling lithium responsiveness in a dish. Nat Rev Neurosci 16, 703 (2015). https://doi.org/10.1038/nrn4062

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