Neurons differentiated from BP iPSC were significantly different in their gene expression profile from those derived from control iPSC. BP neurons expressed more membrane receptors and ion channel genes than control neurons, particularly transcripts involved in calcium signaling. Subtle dysregulation of calcium signaling has been suggested to generate inappropriate neuronal responses and enhance the tonic excitability that maintains brain rhythms in BP.59 Calcium signaling also has a critical role in development, synaptic plasticity and homeostasis of the CNS; misregulation during development can produce subtle but widespread alterations in lineage differentiation and plasticity throughout the nervous system and may influence susceptibility to BP.60 Our preliminary analyses suggest that calcium signaling is also altered in BP neurons and is sensitive to lithium pretreatment. Lithium acts both pre- and post-synaptically, can alter calcium uptake and intracellular levels, and via GSK3β can be neuroprotective. It will now be possible to examine the detailed effects of lithium exposure as well as effects of other BP drugs and other signaling pathways in these cells.
