title: Cellular models to study bipolar disorder: A systematic review.
abstract: BACKGROUND
  There is an emerging interest in the use of cellular models to study psychiatric disorders. We have systematically reviewed the application of cellular models to understand the biological basis of bipolar disorder (BD).
  
  
  METHODS
  Published scientific literature in MEDLINE, PsychINFO and SCOPUS databases were identified with the following search strategy: [(Lymphoblastoid OR Lymphoblast OR Fibroblast OR Pluripotent OR Olfactory epithelium OR Olfactory mucosa) AND (Bipolar disorder OR Lithium OR Valproate OR Mania)]. Studies were included if they had used cell cultures derived from BD patients.
  
  
  RESULTS
  There were 65 articles on lymphoblastoid cell lines, 14 articles on fibroblasts, 4 articles on olfactory neuronal epithelium (ONE) and 2 articles on neurons reprogrammed from induced pluripotent stem cell lines (IPSC). Several parameters have been studied, and the most replicated findings are abnormalities in calcium signaling, endoplasmic reticulum (ER) stress response, mitochondrial oxidative pathway, membrane ion channels, circadian system and apoptosis related genes. These, although present in basal state, seem to be accentuated in the presence of cellular stressors (e.g. oxidative stress--rotenone; ER stress--thapsigargin), and are often reversed with in-vitro lithium.
  
  
  CONCLUSIONS
  Cellular modeling has proven useful in BD, and potential pathways, especially in cellular resilience related mechanisms have been identified. These findings show consistency with other study designs (genome-wide association, brain-imaging, and post-mortem brain expression). ONE cells and IPSC reprogrammed neurons represent the next generation of cell models in BD. Future studies should focus on family-based study designs and combine cell models with deep sequencing and genetic manipulations.
authors.affiliation: Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bangalore, India; National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India; Centre for Brain Development and Repair, Institute of Stem Cell Biology and Regenerative Medicine, Bangalore, India.
authors.forename: Biju
authors.initials: B
authors.lastname: Viswanath
authors.affiliation: Department of Psychiatry, Elite Mission Hospital, Koorkanchery, Thrissur, Kerala, India.
authors.forename: Sam P
authors.initials: SP
authors.lastname: Jose
authors.affiliation: Laboratory of Pharmacogenomics, Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Squassina
authors.affiliation: Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
authors.forename: Jagadisha
authors.initials: J
authors.lastname: Thirthalli
authors.affiliation: Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
authors.forename: Meera
authors.initials: M
authors.lastname: Purushottam
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India.
authors.forename: Odity
authors.initials: O
authors.lastname: Mukherjee
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vladimirov
authors.affiliation: University of Patras, School of Health Sciences, Department of Pharmacy, Patras, Greece.
authors.forename: George P
authors.initials: GP
authors.lastname: Patrinos
authors.affiliation: Laboratory of Pharmacogenomics, Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy; Unit of Clinical Pharmacology, Teaching Hospital, Cagliari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Del Zompo
authors.affiliation: Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bangalore, India; National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India. Electronic address: sjain.nimhans@gmail.com.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Jain
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use; D017209:Apoptosis; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D018020:Lithium Compounds / Q000627:therapeutic use; D008214:Lymphocytes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D015398:Signal Transduction; D014635:Valproic Acid / Q000627:therapeutic use
chemical_list: D014150:Antipsychotic Agents; D007473:Ion Channels; D018020:Lithium Compounds; D014635:Valproic Acid; D002118:Calcium
keywords: Bipolar disorder; Cell model; Fibroblast; Lymphoblast; Olfactory; Pluripotent