Hippocampus-dependent memory and allele-specific gene expression in adult offspring of alcohol-consuming dams after neonatal treatment with thyroxin or metformin
Fetal alcohol spectrum disorder (FASD), the result of fetal alcohol exposure (FAE), affects 2–11% of children worldwide, with no effective treatments. Hippocampus-based learning and memory deficits are key symptoms of FASD. Our previous studies show hypothyroxinemia and hyperglycemia of the alcohol-...
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Veröffentlicht in: | Molecular psychiatry 2018-07, Vol.23 (7), p.1643-1651 |
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Zusammenfassung: | Fetal alcohol spectrum disorder (FASD), the result of fetal alcohol exposure (FAE), affects 2–11% of children worldwide, with no effective treatments. Hippocampus-based learning and memory deficits are key symptoms of FASD. Our previous studies show hypothyroxinemia and hyperglycemia of the alcohol-consuming pregnant rat, which likely affects fetal neurodevelopment. We administered vehicle, thyroxine (T4) or metformin to neonatal rats post FAE and rats were tested in the hippocampus-dependent contextual fear-conditioning paradigm in adulthood. Both T4 and metformin alleviated contextual fear memory deficit induced by FAE, and reversed the hippocampal expression changes in the thyroid hormone-inactivating enzyme, deiodinase-III (
Dio3
) and insulin-like growth factor 2 (
Igf2
), genes that are known to modulate memory processes. Neonatal T4 restored maternal allelic expressions of the imprinted
Dio3
and
Igf2
in the adult male hippocampus, while metformin restored FAE-caused changes in
Igf2
expression only. The decreased hippocampal expression of DNA methyltransferase 1 (
Dnmt1
) that maintains the imprinting of
Dio3
and
Igf2
during development was normalized by both treatments. Administering Dnmt1 inhibitor to control neonates resulted in FAE-like deficits in fear memory and hippocampal allele-specific expression of
Igf2
, which were reversed by metformin. We propose that neonatal administration of T4 and metformin post FAE affect memory via elevating
Dnmt1
and consequently normalizing hippocampal
Dio3
and
Igf2
expressions in the adult offspring. The present results indicate that T4 and metformin, administered during the neonatal period that is equivalent to the third trimester of human pregnancy, are potential treatments for FASD and conceivably for other neurodevelopmental disorders with cognitive deficits. |
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ISSN: | 1359-4184 1476-5578 |
DOI: | 10.1038/mp.2017.129 |