Elevated dopamine levels during gestation produce region-specific decreases in neurogenesis and subtle deficits in neuronal numbers.
Dopamine levels in the fetal brain were increased by administering the dopamine precursor 3,4-dihydroxy-l-phenylalanine (l-DOPA) to pregnant mice in drinking water. The l-DOPA exposure decreased bromodeoxyuridine (BrdU) labeling in the lateral ganglionic eminence and frontal cortical neuroepithelium but not medial or caudal ganglionic eminences. The regional differences appear to reflect heterogeneity in precursor cells' responses to dopamine receptor activation. Relative numbers of E15-generated neurons were decreased at postnatal day 21 (P21) in the caudate-putamen, nucleus accumbens and frontal cortex but not globus pallidus in the l-DOPA group. TUNEL labeling did not show significant differences on P0, P7 or P14 in the caudate-putamen or frontal cortex, suggesting that cell death was not altered. Although virtually all cells in the P21 brains that were labeled with the E15 BrdU injection were NeuN-positive, stereological analyses showed no significant changes in total numbers of NeuN-positive or NeuN-negative cells in the P21 caudate-putamen or frontal cortex. Thus persisting deficits in neuronal numbers were evident in the l-DOPA group only by birth-dating analyses and not upon gross histological examination of brain sections or analysis of total numbers of neurons or glia. One explanation for this apparent discrepancy is that l-DOPA exposure decreased cell proliferation at E15 but not at E13. By E15, expansion of the neuroepithelial precursor pool is complete and any decrease in cell proliferation likely produces only marginal decreases in the total numbers of cells generated. Our l-DOPA exposure model may be pertinent to investigations of neurological dysfunction produced by developmental dopamine imbalance.
McCarthy
Deirdre
D
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA.
Lueras
Paula
P
Bhide
Pradeep G
PG
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000008:administration & dosage; D001205:Ascorbic Acid / Q000008:administration & dosage; D001552:Benzazepines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D016923:Cell Death; D049109:Cell Proliferation / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000008:administration & dosage; D004622:Embryo, Mammalian; D005260:Female; D020287:In Situ Nick-End Labeling; D007980:Levodopa / Q000008:administration & dosage; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011247:Pregnancy; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000975:Antioxidants; D001552:Benzazepines; D015259:Dopamine Agents; D007980:Levodopa; C067113:SK&F 81297; D014446:Tyrosine 3-Monooxygenase; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine; D001205:Ascorbic Acid; D004298:Dopamine