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Schlagwörter:
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Zusammenfassung:
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.
