Mouse maternal protein restriction around conception and during gestation permanently alters brain cytoarchitecture and memory

Abstract

Poor maternal nutrition during pregnancy is detrimental to foetal development and increases the risk of chronic diseases in later life, including neurological disorders such as schizophrenia. Previous studies have shown that diet restriction during gestation influences foetal brain development causing structural, biochemical and pathway alterations leading to impaired motor and cognitive function. However, the effect of diet restriction solely during embryogenesis on brain development is unknown. We have previously shown that maternal low protein diet confined to the preimplantation period with normal diet thereafter during gestation and postnatally is sufficient to induce cardiometabolic and locomotory behavioural abnormalities in adult mouse offspring. In this study female mice were fed from mating to term either (1) normal protein diet (NPD), (2) low protein diet (LPD) or (3) embryonic LPD (Emb-LPD; LPD for 0-3.5 days (E3.5), NPD thereafter) and a comprehensive analysis of foetal and adult brain development was performed for each diet. EmbLPD and sustained LPD reduced neural stem cell and progenitor cell numbers through suppressed proliferation rates in both ganglionic eminences and cortex of foetal brain at E12.5, E14.5 and E17.5. Emb-LPD additionally caused rapid differentiation of remaining NSCs resulting in increased differentiated neurons. Emb-LPD adult offspring exhibited a deficit in short-term and long-term memory, whilst only LPD males show poor long-term memory. Female Emb-LPD adult offspring show increased cortical thickness, male and female Emb-LPD and sustained LPD showed changes in the proportion of different neuronal populations. Additionally, Emb-LPD and LPD diets affected the glial populations of the hippocampus with increased astrocytic cells in female LPD but a reduction in the Emb-LPD offspring. These data reveal, for the first time, that poor maternal nutrition around conception, even with good nutrition thereafter, compromises fundamental cellular processes coordinating early brain development and differentiation, correlated with adult offspring memory deficits.

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ORCID for Sandrine Willaime: orcid.org/0000-0002-1121-6419

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