Abstract
Prenatal ethanol exposure (PAE) induces behavioral maladptations in offspring, including a deficit in memory formation which is part of the umbrella sign of fetal alcohol spectrum disorder. Clinical and preclinical studies have shown that iron depletion exacerbates cognitive problems in offspring exposed to ethanol in utero and that PAE promotes dysregulation in brain iron homeostasis. However, the mechanisms underlying brain iron dysregulation and neuronal activity defects in adolescent offspring of PAE are unclear and poorly understand. Here, we used a PAE rat model to analyze messenger RNA (mRNA) and protein expression of iron homeostasis genes such as transferrin receptor (TfR), divalent metal transporter (DMT1), ferroportin (FPN1), and ferritin (FT) in brain areas associated with memory formation such as the prefrontal cortex (PFC), ventral tegmental area, and hippocampus. Interestingly, we found that 21 day old PAE rats have higher mRNA expression of DMT1 in the PFC, and TfR in the hippocampus, compared to control animals. In contrast FPN has lower mRNA expression in the PFC, and FT and FPN1 have lower expression in the hippocampus. In agreement with these results, we found a 1.5–2 fold increase of TfR and DMT1 protein levels both in the hippocampus and the PFC. Additionally, using an electrophysiological approach, we found that in hippocampal slices from PAE rats, iron treatment decreased long-term potentiation (LTP), but not AMPAR basal transmission (AMPAR fEPSP). In contrast, in control slices Fe-NTA did not affect LTP but decreased significantly the AMPAR fEPSP. Meanwhile, iron chelation with deferiprone decreased AMPAR transmission in PAE and control slices and decreased LTP only in controls slices. These results suggest that PAE affects iron homeostasis of specific brain areas—PFC and hippocampus—which could be involved in maladaptive cognition observed in this animal model.
Highlights
The consumption of alcohol during pregnancy significantly alters fetal development and growth (Cuzon et al, 2008), and affects cognitive processes throughout the child’s life (Ramsay, 2010; Skorput et al, 2015)
Brain iron homeostasis is a complex processes modulated by several proteins which are expressed in the brain, including divalent metal transporter 1 (DMT1) isoforms, transferrin receptor (TfR), FT, ferroportin 1 (FPN), and the HAMP (Hentze et al, 2004; Ke et al, 2005; Singh et al, 2014)
At postnatal day 21 (P21) the isoform DMT1 (−) iron-response element (IRE) and (+) IRE are expressed at higher levels in the ventral tegmental area (VTA) compared to the hippocampus (p = 0.0009, p = 0.0005, respectively); HAMP messenger RNA (mRNA) are expressed in higher levels in the VTA compared to the hippocampus (p = 0.00001); FPN are expressed in higher levels in the hippocampus compared to the prefrontal cortex (PFC) (p = 0.0235)
Summary
The consumption of alcohol during pregnancy significantly alters fetal development and growth (Cuzon et al, 2008), and affects cognitive processes throughout the child’s life (Ramsay, 2010; Skorput et al, 2015). These studies have focused on iron homeostasis in the whole brain during the gestational stage (Huebner et al, 2016), and in midbrain and subcortical areas during the postnatal (P17) stage of the offspring (Miller et al, 1995) It is unknown whether PAE affects iron homeostasis and/or neuronal activity in brain areas related with cognitive processes such as the prefrontal cortex (PFC) (Eichenbaum, 2017), the hippocampus (Burgess et al, 2002) and the ventral tegmental area (VTA) (Lisman and Grace, 2005) in adolescent animals
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
