title: Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder.
abstract: Subtle mood fluctuations are normal emotional experiences, whereas drastic mood swings can be a manifestation of bipolar disorder (BPD). Despite their importance for normal and pathological behavior, the mechanisms underlying endogenous mood instability are largely unknown. During embryogenesis, the transcription factor Otx2 orchestrates the genetic networks directing the specification of dopaminergic (DA) and serotonergic (5-HT) neurons. Here we behaviorally phenotyped mouse mutants overexpressing Otx2 in the hindbrain, resulting in an increased number of DA neurons and a decreased number of 5-HT neurons in both developing and mature animals. Over the course of 1 month, control animals exhibited stable locomotor activity in their home cages, whereas mutants showed extended periods of elevated or decreased activity relative to their individual average. Additional behavioral paradigms, testing for manic- and depressive-like behavior, demonstrated that mutants showed an increase in intra-individual fluctuations in locomotor activity, habituation, risk-taking behavioral parameters, social interaction, and hedonic-like behavior. Olanzapine, lithium, and carbamazepine ameliorated the behavioral alterations of the mutants, as did the mixed serotonin receptor agonist quipazine and the specific 5-HT2C receptor agonist CP-809101. Testing the relevance of the genetic networks specifying monoaminergic neurons for BPD in humans, we applied an interval-based enrichment analysis tool for genome-wide association studies. We observed that the genes specifying DA and 5-HT neurons exhibit a significant level of aggregated association with BPD but not with schizophrenia or major depressive disorder. The results of our translational study suggest that aberrant development of monoaminergic neurons leads to mood fluctuations and may be associated with BPD.
authors.affiliation: Department of Physiology and Cell Biology, Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
authors.forename: Marin M
authors.initials: MM
authors.lastname: Jukic
authors.affiliation: 1] The Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany [2] Faculty of Biology, Ludwig-Maximilian University of Munich, Munich, Germany.
authors.forename: Tania
authors.initials: T
authors.lastname: Carrillo-Roa
authors.affiliation: Department of Physiology and Cell Biology, Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Bar
authors.affiliation: Department of Physiology and Cell Biology, Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
authors.forename: Gal
authors.initials: G
authors.lastname: Becker
authors.affiliation: Department of Physiology and Cell Biology, Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
authors.forename: Vukasin M
authors.initials: VM
authors.lastname: Jovanovic
authors.affiliation: Department of Physiology and Cell Biology, Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
authors.forename: Ksenija
authors.initials: K
authors.lastname: Zega
authors.affiliation: The Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.affiliation: Department of Physiology and Cell Biology, Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
authors.forename: Claude
authors.initials: C
authors.lastname: Brodski
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D015306:Biogenic Monoamines / Q000378:metabolism*; D001714:Bipolar Disorder / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D003623:Dark Adaptation / Q000187:drug effects / Q000235:genetics; D002658:Developmental Disabilities / Q000150:complications* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D019964:Mood Disorders / Q000188:drug therapy / Q000209:etiology*; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D051857:Otx Transcription Factors / Q000378:metabolism; D018490:Serotonin Agents / Q000627:therapeutic use
chemical_list: D000928:Antidepressive Agents; D015306:Biogenic Monoamines; C080330:En1 protein, mouse; D018398:Homeodomain Proteins; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; D018490:Serotonin Agents