Intrauterine Growth Restriction Alters Postnatal Hippocampal Dentate Gyrus Neuron and Microglia Morphology and Cytokine/Chemokine Milieu in Mice

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Abstract
Infants born with intrauterine growth restriction (IUGR) have up to a five-fold higher risk of learning and memory impairment than those with normal growth. Using a mouse model of hypertensive diseases of pregnancy (HDP) to replicate uteroplacental insufficiency (UPI), we have previously shown that UPI causes premature embryonic hippocampal dentate gyrus (DG) neurogenesis in IUGR offspring. The DG is a brain region that receives the first cortical information for memory formation. In the current study, we examined the postnatal DG neuron morphology one month after delivery (P28) using recombinant adeno-associated viral labeling of neurons. We also examined DG microglia’s morphology using immunofluorescent histochemistry and defined the hippocampal cytokine/chemokine milieu using Luminex xMAP technology. We found that IUGR preserved the principal dendrite lengths but decreased the dendritic branching and volume of DG neurons. IUGR augmented DG microglial number and cell size. Lastly, IUGR altered the hippocampal cytokine/chemokine profile in a sex-specific manner. We conclude that the prematurely-generated neuronal progenitors develop abnormal morphologies postnatally in a cell-autonomous manner. Microglia appear to modulate neuronal morphology by interacting with dendrites amidst a complex cytokine/chemokine environment that could ultimately lead to adult learning and memory deficits in our mouse model.

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