Preliminary evidence for a modulation of fetal dopaminergic development by maternal immune activation during pregnancy.
Maternal infection during pregnancy is an environmental risk factor for the offspring to develop severe brain disorders, including schizophrenia and autism. However, only little is known about the neurodevelopmental mechanisms underlying the association between prenatal exposure to infection and the emergence of brain and behavioral dysfunctions in later life. Using a mouse model of prenatal immune challenge by the viral mimic polyriboinosinic-polyribocytidilic acid (PolyI:C), we explored the acute effects of maternal immune activation during pregnancy on the development of the fetal dopaminergic system, a neurotransmitter system known to be affected in schizophrenia and related disorders. We found that maternal immunological stimulation in early/middle pregnancy increased the number of mesencephalic dopamine neurons in the fetal brain at middle/late and late gestation. This effect was paralleled by changes in fetal expression of several genes known to be involved in dopamine neuron development, including the inductive signals sonic hedgehog (Shh) and fibroblast growth factor 8 (Fgf8), as well as transcription factors Nurr1 and Pitx3. These findings provide initial in vivo evidence for a modulation of fetal dopaminergic development by maternal immune activation during pregnancy. Additional investigations of the neurodevelopmental effects of prenatal immune challenge are thus clearly warranted in order to further validate whether abnormal dopaminergic development may be a critical neuropathological mechanism underlying the precipitation of schizophrenia-like brain and behavioral dysfunctions emerging after in utero exposure to infection.
Meyer
U
U
Laboratory of Behavioural Neurobiology, ETH Zurich, Schorenstrasse 16, Schwerzenbach, Switzerland. urmeyer@ethz.ch
Engler
A
A
Weber
L
L
Schedlowski
M
M
Feldon
J
J
D000818:Animals; D000941:Antigens / Q000276:immunology; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis; D004298:Dopamine / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005260:Female; D047109:Fetal Development / Q000502:physiology*; D005333:Fetus / Q000276:immunology* / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D008636:Mesencephalon / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000276:immunology; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000276:immunology* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000941:Antigens; D016207:Cytokines; D050483:Dopamine Plasma Membrane Transport Proteins; D014446:Tyrosine 3-Monooxygenase; D011070:Poly I-C; D004298:Dopamine