Neurodevelopmental origins of bipolar disorder: iPSC models

• Published in: Molecular and cellular neuroscience Vol. 73; pp. 63 - 83
• Main Authors: O'Shea, K. Sue, McInnis, Melvin G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2016
• Subjects: Astrocyte; Autism; Bipolar Disorder - genetics; Bipolar Disorder - metabolism; Bipolar Disorder - pathology; Calcium Signaling; Cell Culture Techniques - methods; Cortex; Depression; Development; Epigenetics; Gene expression; Glia; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Mania; Microarray; Models, Biological; Mood disorder; Neurogenesis; Neuron; Oligodendrocyte; Schizophrenia; Stem cell; Telencephalon; Transcriptome; C; VZ; Stem cell; Schizophrenia; CNS; MDD; PFC; Microarray; BP; iNs; iPSCs; ASD; SHH; Oligodendrocyte; Development; Mood disorder; DLPFC; BDNF; ONPs; SZ; Cortex; Telencephalon; Depression; MGE; Astrocyte; Gene expression; PCA; Autism; Neuron; NPCs; Epigenetics; Mania; hESCs; Glia; LCLs; BA
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2015.11.006

Bipolar disorder (BP) is a chronic neuropsychiatric condition characterized by pathological fluctuations in mood from mania to depression. Adoption, twin and family studies have consistently identified a significant hereditary component to BP, yet there is no clear genetic event or consistent neuropathology. BP has been suggested to have a developmental origin, although this hypothesis has been difficult to test since there are no viable neurons or glial cells to analyze, and research has relied largely on postmortem brain, behavioral and imaging studies, or has examined proxy tissues including saliva, olfactory epithelium and blood cells. Neurodevelopmental factors, particularly pathways related to nervous system development, cell migration, extracellular matrix, H3K4 methylation, and calcium signaling have been identified in large gene expression and GWAS studies as altered in BP. Recent advances in stem cell biology, particularly the ability to reprogram adult somatic tissues to a pluripotent state, now make it possible to interrogate these pathways in viable cell models. A number of induced pluripotent stem cell (iPSC) lines from BP patient and healthy control (C) individuals have been derived in several laboratories, and their ability to form cortical neurons examined. Early studies suggest differences in activity, calcium signaling, blocks to neuronal differentiation, and changes in neuronal, and possibly glial, lineage specification. Initial observations suggest that differentiation of BP patient-derived neurons to dorsal telencephalic derivatives may be impaired, possibly due to alterations in WNT, Hedgehog or Nodal pathway signaling. These investigations strongly support a developmental contribution to BP and identify novel pathways, mechanisms and opportunities for improved treatments. •Bipolar disorder (BP) critically requires cell-based models.•We review the data that suggest that BP has strong developmental underpinnings.•Gene expression analyses identify developmental pathways, calcium signaling.•Induced pluripotent stem cells offer a new opportunity to model BP.•Early studies identify differences in neuronal differentiation and activity.