Bilirubin as a determinant for altered neurogenesis, neuritogenesis, and synaptogenesis.
Elevated levels of serum unconjugated bilirubin (UCB) in the first weeks of life may lead to long-term neurologic impairment. We previously reported that an early exposure of developing neurons to UCB, in conditions mimicking moderate to severe neonatal jaundice, leads to neuritic atrophy and cell death. Here, we have further analyzed the effect of UCB on nerve cell differentiation and neuronal development, addressing how UCB may affect the viability of undifferentiated neural precursor cells and their fate decisions, as well as the development of hippocampal neurons in terms of dendritic and axonal elongation and branching, the axonal growth cone morphology, and the establishment of dendritic spines and synapses. Our results indicate that UCB reduces the viability of proliferating neural precursors, decreases neurogenesis without affecting astrogliogenesis, and increases cellular dysfunction in differentiating cells. In addition, an early exposure of neurons to UCB decreases the number of dendritic and axonal branches at 3 and 9 days in vitro (DIV), and a higher number of neurons showed a smaller growth cone area. UCB-treated neurons also reveal a decreased density of dendritic spines and synapses at 21 DIV. Such deleterious role of UCB in neuronal differentiation, development, and plasticity may compromise the performance of the brain in later life.
Fernandes
Adelaide
A
Faculdade de Farmácia, Centro de Patogénese Molecular-iMed.UL, University of Lisbon, Lisbon, Portugal.
Falcão
Ana Sofia
AS
Abranches
Elsa
E
Bekman
Evguenia
E
Henrique
Domingos
D
Lanier
Lorene M
LM
Brites
Dora
D
D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001663:Bilirubin / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014162:Transfection / Q000379:methods
D000975:Antioxidants; D009419:Nerve Tissue Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D049452:Green Fluorescent Proteins; C022616:thiazolyl blue; D001663:Bilirubin