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Mouse maternal protein restriction during preimplantation alone permanently alters brain neuron proportion and adult short-term memory

Gould JM, Smith PJ, Airey CJ, Mort EJ, Airey LE, Warricker FDM, Pearson-Farr JE, Weston EC, Gould PJW, Semmence OG, Restall KL, Watts JA, McHugh PC, Smith SJ, Dewing JM, Fleming TP, Willaime-Morawek S (2018) Proc Natl Acad Sci U S A.  2018 Jun.  pii: 201721876. doi: 10.1073/pnas.1721876115. [Epub ahead of print] 

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Abstract:

Maternal protein malnutrition throughout 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 the preimplantation period for brain development is unknown.

We have previously shown that maternal low-protein diet (LPD) confined to the preimplantation period (Emb-LPD) in mice, with normal nutrition thereafter, is sufficient to induce cardiometabolic and locomotory behavioral abnormalities in adult offspring. Here, using a range of in vivo and in vitro techniques, we report that Emb-LPD and sustained LPD reduce neural stem cell (NSC) and progenitor cell numbers at E12.5, E14.5, and E17.5 through suppressed proliferation rates in both ganglionic eminences and cortex of the fetal brain.

Moreover, Emb-LPD causes remaining NSCs to up-regulate the neuronal differentiation rate beyond control levels, whereas in LPD, apoptosis increases to possibly temper neuron formation. Furthermore, Emb-LPD adult offspring maintain the increase in neuron proportion in the cortex, display increased cortex thickness, and exhibit short-term memory deficit analyzed by the novel-object recognition assay. Last, we identify altered expression of fragile X family genes as a potential molecular mechanism for adverse programming of brain development.

Collectively, these data demonstrate that poor maternal nutrition from conception is sufficient to cause abnormal brain development and adult memory loss.

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