Maternal protein restriction around conception reduces the neural stem cells during mouse fetal brain development and alters neuronal differentiation during gestation

Gould, Joanna, Smith, Phoebe J., Airey, Chris J., Warricker, Frazer D.M., Restall, Katie, Egar, J, Marfy-smith, Stephanie J, Dewing, Jennifer, Fleming, Tom and Willaime-Morawek, Sandrine (2016) Maternal protein restriction around conception reduces the neural stem cells during mouse fetal brain development and alters neuronal differentiation during gestation. Reproduction Abstracts. (doi:10.1530/repabs.3.O024).

Abstract

Introduction: maternal malnutrition during pregnancy is detrimental to fetal development and increases the risk of many chronic diseases in later life i.e. neurological consequences such as increased risk of schizophrenia. Previous studies have shown maternal protein malnutrition during pregnancy and lactation compromises brain development in late gestation and after birth, affecting structural, biochemical and pathway dynamics with lasting consequences for motor and cognitive function. However, the importance of nutrition during embryogenesis for early brain development is unknown. We have previously shown maternal low protein diet confined to the preimplantation period (Emb-LPD) in mice is sufficient to induce cardiometabolic and locomotory behavioural abnormalities in adult offspring.Methods: using a diet model, female mice were fed different diets from conception to the end of pregnancy: normal protein diet (NPD), low protein diet (LPD) or embryonic LPD (Emb-LPD: LPD for 3.5 days, NPD thereafter). Fetal brains were analysed at three time points in gestation (E12.5, E14.5 & E17.5), with in vivo analysis using FACS and immunofluorescence for neural stem cell and neuron markers, and in vitro techniques using the neurosphere culture assay. We have also carried out a number of follow up behavioural tests for memory including novel object recognition in adult offspring.Results & discussion: we have shown that Emb-LPD and sustained LPD reduce neural stem cell (NSC) and progenitor cell numbers through suppressed proliferation rates in both ganglionic eminences and cortex of the fetal brain at E12.5, E14.5 & E17.5. Moreover, Emb-LPD causes remaining NSCs to upregulate the neuronal differentiation rate in compensation beyond control levels. We have also seen a deficit in short term memory in the Emb-LPD adult offspring. This data is the first to clearly demonstrate that poor maternal nutrition around conception has adverse effects on early brain development, which might be associated with the adult behavioural deficits.

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Contributors

Author: Sandrine Willaime-Morawek

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