Early Developmental Marginal Zinc Deficiency Affects Neurogenesis Decreasing Neuronal Number and Altering Neuronal Specification in the Adult Rat Brain.

Ana M Adamo,Patricia Mathieu,Patricia I Oteiza,Suangsuda Supasai,Xiuzhen Liu,Johnathan R Nuttall

doi:10.3389/fncel.2019.00062

Abstract

During pregnancy, a decreased availability of zinc to the fetus can disrupt the development of the central nervous system leading to defects ranging from severe malformations to subtle neurological and cognitive effects. We previously found that marginal zinc deficiency down-regulates the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and affects neural progenitor cell (NPC) proliferation. This study investigated if marginal zinc deficiency during gestation in rats could disrupt fetal neurogenesis and affect the number and specification of neurons in the adult offspring brain cortex. Rats were fed a marginal zinc deficient or adequate diet throughout gestation and until postnatal day (P) 2, and subsequently the zinc adequate diet until P56. Neurogenesis was evaluated in the offspring at embryonic day (E)14, E19, P2, and P56 measuring parameters of NPC proliferation and differentiation by Western blot and/or immunofluorescence. At E14 and E19, major signals (i.e., ERK1/2, Sox2, and Pax6) that stimulate NPC proliferation and self-renewal were markedly downregulated in the marginal zinc deficient fetal brain. These alterations were associated to a lower number of Ki67 positive cells in the ventricular (VZs) and subventricular zones (SVZs). Following the progression of NPCs into intermediate progenitor cells (IPCs) and into neurons, Pax6, Tbr2 and Tbr1 were affected in the corresponding areas of the brain at E19 and P2. The above signaling alterations led to a lower density of neurons and a selective decrease of glutamatergic neurons in the young adult brain cortex exposed to maternal marginal zinc deficiency from E14 to P2. Current results supports the concept that marginal zinc deficiency during fetal development can disrupt neurogenesis and alter cortical structure potentially leading to irreversible neurobehavioral impairments later in life.

Highlights

Prenatal zinc deficiency resulting from insufficient dietary intake, absorption, or transport can compromise development of the central nervous system leading to a spectrum of defects ranging from severe congenital malformations to subtle neurological and cognitive impairments
Given our previous work showing a decrease in extracellular signal-regulated kinase 1/2 (ERK1/2) activation together with a reduction in neural progenitor cell (NPC) proliferation, we aimed to investigate the impact of these events on cortical excitatory neurons
Results from this study demonstrate that a decreased proliferation of NPCs resulting from gestational marginal zinc deficiency leads to the disruption of cortical neurogenesis in the rat offspring brain

Summary

Introduction

Prenatal zinc deficiency resulting from insufficient dietary intake, absorption, or transport can compromise development of the central nervous system leading to a spectrum of defects ranging from severe congenital malformations to subtle neurological and cognitive impairments. Severe zinc deficiency during fetal development has been implicated as a mechanism contributing to neural tube defects (NTDs). Severe dietary zinc deficiency in rats during pregnancy leads to NTDs in association with decreased cell proliferation in the ventricular zone (VZ) of the fetal brain (Swenerton et al, 1969). Developmental marginal zinc deficiency does not cause gross malformations like NTDs, it is associated with neurological morbidity such as impairments in learning, working memory, and social behavior (Hagmeyer et al, 2015). Similar cognitive defects result from secondary zinc deficiency caused by gestational exposure to infection in rats (Kirsten et al, 2015)

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