Intrauterine Growth Restriction Disrupts the Postnatal Critical Period of Synaptic Plasticity in the Mouse Dorsal Hippocampus in a Model of Hypertensive Disease of Pregnancy.

INTRODUCTION: Intrauterine growth restriction (IUGR) from hypertensive disease of pregnancy complicates up to 10% of all pregnancies. Significant hippocampal-dependent cognitive and memory impairments as well as neuropsychiatric disorders have been linked to IUGR. Because disturbance of the hippocampal critical period (CPd) of synaptic plasticity leads to impairments similar to those described in IUGR human offspring, we hypothesized that IUGR would perturb the CPd of synaptic plasticity in the mouse hippocampus in our model. METHODS: IUGR was produced by a micro-osmotic pump infusion of the potent vasoconstrictor U-46619, a thromboxane A2-agonist, at embryonic day 12.5 in C57BL/6J mouse dams to precipitate hypertensive disease of pregnancy and IUGR. Sham-operated mice acted as controls. At P10, P18, and P40, we assessed astrogliosis using GFAP-IHC. In dorsal CA1 and CA3 subfields, we assessed the immunoreactivities (IR) (IF-IHC) to (i) parvalbumin (PV) and glutamate decarboxylase (GAD) 65/67, involved in CPd onset; (ii) PSA-NCAM that antagonizes CPd onset; (iii) NPTX2, necessary for excitatory synapse formation and engagement of CPd; and (iv) MBP and WFA, staining perineural nets (PNNs), marking CPd closure. ImageJ/Fiji and IMARIS were used for image processing and SPSS v24 for statistical analysis. RESULTS: Although PV+ interneuron numbers and IR intensity were unchanged, development of GAD65/67+ synaptic boutons was accelerated at P18 IUGR mice and inversely correlated with decreased expression of PSA-NCAM in the CA of P18 IUGR mice at P18. NPTX2+ puncta and total volume were persistently decreased in the CA3 pyramidal and radiatum layers of IUGR mice from P18 to P40. At P40, axonal myelination (MBP+) in CA3 of IUGR mice was decreased and correlated with NPTX2 deficits. Lastly, the volume and integrity of the PNNs in the dorsal CA was disrupted in IUGR mice at P40. DISCUSSION/CONCLUSION: IUGR disrupts the molecular and structural initiation, consolidation, and closure of the CPd of synaptic plasticity in the mouse hippocampus in our model, which may explain the learning and memory deficits observed in juvenile IUGR mice and the cognitive disorders seen in human IUGR offspring. The mechanistic links warrant further investigation, to identify therapeutic targets to prevent neurodevelopmental deficits in patients affected by IUGR.

Dysregulation of ErbB4 Signaling Pathway in the Dorsal Hippocampus after Neonatal Hypoxia-Ischemia and Late Deficits in PV+ Interneurons, Synaptic Plasticity and Working Memory.

Neonatal hypoxic-ischemic (HI) injury leads to deficits in hippocampal parvalbumin (PV)+ interneurons (INs) and working memory. Therapeutic hypothermia (TH) does not prevent these deficits. ErbB4 supports maturation and maintenance of PV+ IN. Thus, we hypothesized that neonatal HI leads to persistent deficits in PV+ INs, working memory and synaptic plasticity associated with ErbB4 dysregulation despite TH. P10 HI-injured mice were randomized to normothermia (NT, 36 °C) or TH (31 °C) for 4 h and compared to sham. Hippocampi were studied for α-fodrin, glial fibrillary acidic protein (GFAP), and neuroregulin (Nrg) 1 levels; erb-b2 receptor tyrosine kinase 4 (ErbB4)/ Ak strain transforming (Akt) activation; and PV, synaptotagmin (Syt) 2, vesicular-glutamate transporter (VGlut) 2, Nrg1, and ErbB4 expression in coronal sections. Extracellular field potentials and behavioral testing were performed. At P40, deficits in PV+ INs correlated with impaired memory and coincided with blunted long-term depression (LTD), heightened long-term potentiation (LTP) and increased Vglut2/Syt2 ratio, supporting excitatory-inhibitory (E/I) imbalance. Hippocampal Nrg1 levels were increased in the hippocampus 24 h after neonatal HI, delaying the decline documented in shams. Paradoxically ErbB4 activation decreased 24 h and again 30 days after HI. Neonatal HI leads to persistent deficits in hippocampal PV+ INs, memory, and synaptic plasticity. While acute decreased ErbB4 activation supports impaired maturation and survival after HI, late deficit reemergence may impair PV+ INs maintenance after HI.