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Published on: November 20, 2015
Impaired Organization of GABAergic Neurons Following Prenatal Hypoxia
Haya Nisimov1, Ayelet Orenbuch1, Samuel J Pleasure2
1Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.
Insights
Early-life hypoxia causes significant cortical interneuron loss and mispositioning in mice. These events, linked to altered guidance molecules, may underlie later-life neuropsychiatric conditions.
Area of Science:
- Neuroscience
- Developmental Biology
- Perinatal Medicine
Background:
- Intrauterine conditions, including perinatal hypoxia-ischemia, are linked to later neuropsychiatric disorders.
- Preterm infants with very low birth weight are highly susceptible to hypoxic insults.
- GABA pathway dysfunction in the brain is associated with these conditions.
Purpose of the Study:
- To investigate the origin of GABAergic cell loss following early-life hypoxia.
- To determine if mispositioning of neurons during cerebral cortex formation contributes to cell loss.
- To explore the molecular mechanisms underlying these developmental changes.
Main Methods:
- Exposing C57 black mice to hypoxic conditions (9% O2; 3% CO2).
- Quantifying cortical cell loss and assessing neuronal migration in the developing cortex.
- Analyzing changes in guidance molecules (HIF-1α, reelin) and radial glia organization.
Main Results:
- Hypoxia caused 22-26% cell loss in the cortical plate within four days.
- Surviving neurons failed to migrate to correct cortical layers.
- Differential sensitivity to hypoxia based on germinal zone origin and location was observed.
- Altered levels and distribution of guidance molecules and radial glia organization were detected.
Conclusions:
- Early-life hypoxia leads to significant interneuron loss and migration defects in the developing cerebral cortex.
- Changes in the molecular environment, including guidance molecules and radial glia, likely contribute to these outcomes.
- These early developmental disruptions may be a precursor to later-life neuropsychiatric conditions.
Abstract:
Several conditions related to the intrauterine environment are associated with neuropsychiatric conditions in later life. In humans, approximately 2% of infants are exposed to perinatal hypoxia-ischemia or prolonged anoxic insult, a condition to which very low birth weight preterm infants exhibit the highest susceptibility. Analyses of postmortem tissue link some presentations of these conditions to changes in GABA pathway functionality in the brains of affected subjects. Using animal models of early-life hypoxia-ischemia, losses of particular interneuron populations were reported. We hypothesize that the origin of GABAergic cell loss is in the mispositioning of neurons during the formation of the cerebral cortex. Here we report that in C57 black mice exposed to hypoxic conditions (9% O2; 3% CO2), 22-26% of cell loss was detected in the cortical plate as early as four days after the hypoxic event. Moreover, the surviving cells failed to populate the proper layers in the developing cortex. Differential sensitivities were observed in neurons that originated from different germinal zones. A significant effect of GABAergic cell location along the anterior-posterior and medio-lateral axes on neuron sensitivity to hypoxia was detected. Finally, changes in guidance molecules in the developing cortex, including increases in hypoxia-inducible factor 1-alpha levels and intracellular distribution, decreases in reelin levels in the cortical plate and altered organization of radial glia, were observed. These changes in the molecular landscape of the immediate environment of the immature neurons may contribute to the observed outcomes in neuronal migration to, and establishment in, the correct cortical layers. We suggest that the interneuron loss may be related to these early events.
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