Gestational Iron Deficiency disrupts neural patterning in the embryo

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Abstract This supplemental funding request builds on our EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT-sponsored research grant that is focused on the impact of gestational iron deficiency (GID) on brain development. In the course of this work we have discovered that GID alters neuronal cell populations in the embryonic brain which result in an altered balance of excitatory and inhibitory signaling (E/I balance) later in life. This imbalance, which is associated with a decrease in parvalbumin expressing interneurons (PV) is refractory to postnatal iron supplementation suggesting that the changes that occur in the embryo are permanent and might render the brain vulnerable to other insults later in life. Interestingly, recent studies have found that Alzheimer disease is also associated with an impaired E/I balance and mouse models of Alzheimer disease show a significant reduction in the number of PV- expressing cells in the cortex compared with age-matched wild-type counterparts. These observations, together with our recent findings that GID causes region specific dysregulation of metals in the brain (which is also found in AD), raise the interesting hypothesis that gestational iron deficiency renders offspring more susceptible to Alzheimer disease later in life. We will test this novel hypothesis by establishing double-insult models where we expose animal models of familial AD to GID and test whether GID alters the time of onset of pathology and the severity of AD pathology. As a positive control, we will also combine AD mouse models with our newly generated mouse model of early-life exposure to latent human herpes virus 6 infections (HHV6), a secondary insult that has recently been linked to AD and has been suggested to be a pathology modulator.