Effects of intrauterine growth restriction on embryonic hippocampal dentate gyrus neurogenesis and postnatal critical period of synaptic plasticity that govern learning and memory function

Abstract

Intrauterine growth restriction (IUGR) complicates up to 10% of human pregnancies and is the second leading cause of perinatal morbidity and mortality after prematurity. The most common etiology of IUGR in developed countries is uteroplacental insufficiency (UPI). For survivors of IUGR pregnancies, long-term studies consistently show a fivefold increased risk for impaired cognition including learning and memory deficits. Among these, only a few human studies have highlighted sex differences with males and females having differing susceptibilities to different impairments. Moreover, it is well established from brain magnetic resonance imaging that IUGR affects both white and gray matter. The hippocampus, composed of the dentate gyrus (DG) and cornu ammonis (CA) subregions, is an important gray matter structure critical to learning and memory, and is particularly vulnerable to the chronic hypoxic-ischemic effects of UPI. Decreased hippocampal volume is a strong predictor for learning and memory deficits. Decreased neuron number and attenuated dendritic and axonal morphologies in both the DG and CA are additionally seen in animal models. What is largely unexplored is the prenatal changes that predispose an IUGR offspring to postnatal learning and memory deficits. This lack of knowledge will continue to hinder the design of future therapy to improve learning and memory. In this review, we will first present the clinical susceptibilities and human epidemiology data regarding the neurological sequelae after IUGR. We will follow with data generated using our laboratory's mouse model of IUGR, that mimics the human IUGR phenotype, to dissect at the cellular and molecular alterations in embryonic hippocampal DG neurogenesis. We will lastly present a newer topic of postnatal neuron development, namely the critical period of synaptic plasticity that is crucial in achieving an excitatory/inhibitory balance in the developing brain. To our knowledge, these findings are the first to describe the prenatal changes that lead to an alteration in postnatal hippocampal excitatory/inhibitory imbalance, a mechanism that is now recognized to be a cause of neurocognitive/neuropsychiatric disorders in at-risk individuals. Studies are ongoing in our laboratory to elucidate additional mechanisms that underlie IUGR-induced learning and memory impairment and to design therapy aimed at ameliorating such impairment.

Keywords: Wnt signaling; critical period of synaptic plasticity; embryonic neurogenesis; fetal growth restriction; hippocampal dentate gyrus; hypertensive disease of pregnancy; intrauterine growth restriction; learning and memory.

FIGURE 1

Uteroplacental insufficiency (UPI) originating from hypertensive disease of pregnancy (HDP) affects fetal hippocampal dentate gyrus neurogenesis in IUGR offspring which leads to postnatal neuron mal-development and learning and memory deficits. Other organ systems are also affected in this mouse model of IUGR.

FIGURE 2

An illustration summarizing the hippocampal findings in our mouse model of IUGR. During normal embryonic HDG development, neural stem cells give rise to intermediate neuronal progenitors, which migrate tangentially and eventually give rise to Prox1⁺ granule neurons. In the postnatal brain, NSCs reside in the subgranular zone and continue to generate Prox1⁺ granule neurons. The cortical hem, a transient structure formed during development, is the source of a number of patterning morphogens, such as Wnt and BMP proteins, which play critical roles in cell fate specification during hippocampal neurogenesis. In our mouse model of HDP, IUGR was induced at E12.5. At E15.5 (3 days after maternal hypertension), IUGR hippocampus showed decreased canonical and non-canonical Wnt signaling which is accompanied by decreased Sox2⁺ NSC proliferation and depletion. By contrast, IUGR promoted premature neuronal differentiation by increasing % Tbr2⁺ INPs. At E19, % Sox2⁺ NSCs remained diminished but neuron maturation proceeded in an unhindered fashion to generate more NeuroD⁺ neuronal progenitors and Prox1⁺ granule neurons in IUGR. In postnatal life up to day 40, IUGR hippocampi had total volume loss. Novel to the field, IUGR perturbed the critical period of synaptic plasticity to create an excitatory/inhibitory imbalance. AN, ammonic neuroepithelium; CA, cornu ammonis; CH, cortical hem; CTX, cortex; D, dorsal; DNe, dentate neuroepithelium; DG, dentate gyrus; E, embryonic day; F, fimbria; INP, intermediate neuronal progenitor; L, lateral; LGE, lateral ganglionic eminence; M, medial; MGE, medial ganglionic eminence; NSC, neural stem cell; P, postnatal day; SGZ, subgranular zone; V, ventral.

FIGURE 3

The critical period of synaptic plasticity. (A) It is governed by an interaction between the excitatory CA pyramidal cell (denoted as red) and the inhibitory parvalbumin⁺ (PV⁺) interneuron (denoted as green). Opening of the critical period is governed by decreased polysialylation of the neural cell adhesion molecule (PSA-NCAM) in the excitatory pyramidal cell neuronal membranes as well as advanced maturation of PV⁺ interneurons with increased number of glutamate decarboxylase synaptic boutons/axon terminals to result in GABAergic network development. Consolidation of the critical period, on the other hand, is marked by increased neuronal pentraxin 2 (NPTX2) production by CA pyramidal cells, which later localizes to the GluA4 subunit of AMPA receptors on the postsynaptic PV⁺ interneurons. Lastly, closure of the critical period is marked by advanced myelination and formation of perineural nets (PNNs) which support NPTX2’s proximity to PV⁺ interneurons. (B) Regional critical periods of synaptic plasticity progress sequentially in brain development, beginning with the somatosensory cortex, amygdala, then the hippocampus. Postnatal ages at which this sequential maturation of the critical period in normal rodent brain development is delineated at the bottom [adapted from Alberini and Travaglia (2017) and Blair et al. (2010)].