Abstract
Bipolar disorder (BP) is a chronic psychiatric condition characterized by dynamic, pathological mood fluctuations from mania to depression. To date, a major challenge in studying human neuropsychiatric conditions such as BP has been limited access to viable central nervous system tissue to examine disease progression. Patient-derived induced pluripotent stem cells (iPSCs) now offer an opportunity to analyze the full compliment of neural tissues and the prospect of identifying novel disease mechanisms. We have examined changes in gene expression as iPSC derived from well-characterized patients differentiate into neurons; there was little difference in the transcriptome of iPSC, but BP neurons were significantly different than controls in their transcriptional profile. Expression of transcripts for membrane bound receptors and ion channels was significantly increased in BP-derived neurons compared with controls, and we found that lithium pretreatment of BP neurons significantly altered their calcium transient and wave amplitude. The expression of transcription factors involved in the specification of telencephalic neuronal identity was also altered. Control neurons expressed transcripts that confer dorsal telencephalic fate, whereas BP neurons expressed genes involved in the differentiation of ventral (medial ganglionic eminence) regions. Cells were responsive to dorsal/ventral patterning cues, as addition of the Hedgehog (ventral) pathway activator purmorphamine or a dorsalizing agent (lithium) stimulated expression of NKX2-1 (ventral identity) or EMX2 (dorsal) in both groups. Cell-based models should have a significant impact on our understanding of the genesis and therefore treatment of BP; the iPSC cell lines themselves provide an important resource for comparison with other neurodevelopmental disorders.
Highlights
Bipolar disorder (BP) is a severe neuropsychiatric disease characterized by recurrent episodes of manias, pathologically energized states with misguided volition and behavior in a mood state of intoxicating euphoria and depressions that are low moods with compromised energy, volitional states and diminished cognitive capacity
Additional replicated polymorphisms have been identified in Ankyrin 3 (ANK3), which regulates assembly of voltage-gated sodium channels at the node of Ranvier,[14,15] and SYNE1, which has a critical role in synaptic clustering.[16]
The current investigation demonstrates that induced pluripotent stem cells (iPSC) from BP patients are similar to controls (C) in their tri-lineage differentiation capacity and gene expression profiles; the expression of membrane receptors and ion channel transcripts was significantly increased in BP neurons, and different sets of neuronal lineage-specific transcription factors were induced
Summary
Bipolar disorder (BP) is a severe neuropsychiatric disease characterized by recurrent episodes of manias, pathologically energized states with misguided volition and behavior in a mood state of intoxicating euphoria (or irritability) and depressions that are low moods with compromised energy, volitional states and diminished cognitive capacity. Since subtle alterations in developmental pathways can produce neurological consequences that only become apparent much later in life,[25,26] a developmental model to study neuronal differentiation in BP is required. Because they have tri-lineage differentiation potential similar to human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs) provide the. The current investigation demonstrates that iPSC from BP patients are similar to controls (C) in their tri-lineage differentiation capacity and gene expression profiles; the expression of membrane receptors and ion channel transcripts was significantly increased in BP neurons, and different sets of neuronal lineage-specific transcription factors were induced. Differentiation of glia and neurons, as well as an opportunity for comparisons with other neuropsychiatric disorders
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call