Intrauterine growth restriction disturbs the critical period of synaptic plasticity in the hippocampus in a mouse model of hypertensive disease of pregnancy

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ESPR353
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Background: Intrauterine growth restriction (IUGR) complicates up to 15% of all pregnancies, often resulting from hypertensive disease of pregnancy (HDP). Significant cognitive and memory impairments including the future development can be traced back to IUGR. During the critical period (CP) of synaptic plasticity, profound refinement and remodeling of brain circuits occur, which is sculpted by the maturation of the GABAergic network. Thus, any disturbance in the onset and/or closure of this CP specifically in the hippocampus could explain the cognitive and memory impairments linked to IUGR.  

Objective: To study whether IUGR disturbs the onset or closure of the CP of hippocampal synaptic plasticity.

Design/Methods: We induced IUGR by a micro-osmotic pump infusion of U-46619, a thromboxane A2-agonist (TxA), a potent vasoconstrictor, in the last week of C57BL6 pregnant mouse gestation to precipitate HDP. Sham-operated mice were shams. At P18 and P40, we assessed astrogliosis using GFAP-IHC and quantified hippocampal volumes using cresyl-violet staining in sham and TxA hippocampi. In hippocampal CA1,CA3, and dentate gyrus (DG) subfields , we assessed the immunoreactivities (IR) (IF-IHC) to: i) parvalbumin (PV), that triggers  CP onset; ii) PSA-NCAM, that antagonizes CP onset; iii) NPTX2, that engages CP onset; and iv) WFA, that stains perineural nets (PNNs) and marks CP closure. Analysis was stratified by sex. 

Results:  TxA-treated mice developed hippocampal atrophy in the CA1 and CA3 subfields at P18 and P40. However, preliminarily, no differences in astrogliosis (GFAP IHC) or number of PV+ interneurons (IF-IHC) had been identified in the CA1 and CA3 at any time point. At baseline, P18 sham hippocampi had low PSA-NCAM IR in CA1 and CA3 subfields but remained heavily expressed in neuronal progenitor cells of the DG. In contrast, TxA-treated mice showed: i) a modest increase in PSA-NCAM IR in the CA1 and CA3 at P18 compared to sham; ii) a significant deficit in NPTX2 IR in PV+   dendrites in CA1 and CA3 at both P18 and P40; and lastly iii) a disturbed formation of PNN at P40.   

Conclusion: IUGR may disrupt the molecular and structural initiation and consolidation of the CP of synaptic plasticity in the hippocampus in our model of HDP. Although the preserved numbers of PVINs may imply a preserved initiation of the CP, the lack of developmental PSA-NCAM decline and NPTX2 increase argue against an appropriate consolidation of the process. We speculate that this perturbed pattern of synaptic plasticity may underlie the implicit learning and memory deficits observed in our 2 month-old juvenile IUGR offspring.

Johns Hopkins University School of Medicine
Johns Hopkins University
Johns Hopkins University
University of Utah

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