Impaired migration signaling in the hippocampus following prenatal hypoxia.
Prenatal hypoxia ischemia is a major cause of neurodevelopmental impairment in the newborn, associated with risk for motor, behavioral and cognitive impaired outcomes. We used an established mouse model of maternal hypoxia to examine the immediate molecular responses of signaling pathways associated with both cell death and neurogenesis. We also characterized responses to maternal pre-treatment with MgSO(4). Maternal hypoxia at embryonic day 17 (E17) failed to trigger inflammation or cell death in fetal brain at 24 h after hypoxia. However, maternal hypoxia decreased levels of neuronal migration signaling: Reelin (53% of control), Disabled 1 (Dab1, 77% of control), and amyloid precursor protein (APP, 64% of control) 2 h after the insult. These changes persisted for 24 h. At later times, Reelin levels in hippocampi of newborns in the maternal hypoxia-treated group increased compared to controls. Full protection from maternal hypoxia effects on hippocampal Reelin levels resulted from maternal pre-treatment with MgSO(4). Hypoxia and MgSO(4) increased radial and lateral migration distance in the CA1 four days after the insult, while in the DG the hypoxia treatment alone increased migration. Maternal hypoxia and MgSO(4) pre-treatment also stimulated hippocampal expression of genes related to neurogenesis, such as BDNF and NeuroD4. Taken together, the long-term neurodevelopmental outcome of prenatal and perinatal hypoxia may depend on perturbation of developmental signals that affect neuronal migration.
Golan
M Hava
MH
Department of Developmental Molecular Genetics, Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel. havag@bgu.ac.il
Mane
Revital
R
Molczadzki
Gabriela
G
Zuckerman
Michal
M
Kaplan-Louson
Vered
V
Huleihel
Mahmoud
M
Perez-Polo
J Regino
JR
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002491:Central Nervous System Agents / Q000494:pharmacology; D018891:Dentate Gyrus / Q000187:drug effects / Q000196:embryology / Q000503:physiopathology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000196:embryology / Q000503:physiopathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005311:Fetal Hypoxia / Q000188:drug therapy / Q000503:physiopathology*; D006624:Hippocampus / Q000187:drug effects / Q000196:embryology* / Q000503:physiopathology*; D002534:Hypoxia, Brain / Q000188:drug therapy / Q000196:embryology* / Q000503:physiopathology*; D008278:Magnesium Sulfate / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011897:Random Allocation; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
D016564:Amyloid beta-Protein Precursor; D015816:Cell Adhesion Molecules, Neuronal; D002491:Central Nervous System Agents; C103773:Dab1 protein, mouse; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; D008278:Magnesium Sulfate; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases