Brain iron deficiency and affected contextual fear memory in mice with conditional Ferroportin1 ablation in the brain

Abstract

Fear memory is a pivotal biological function by which organisms can predict possible danger to avoid or reduce harm. However, dysregulation of fear memory processing may lead to pathological fear or anxiety and produce serious clinical symptoms, such as post-traumatic stress disorder (PTSD). Iron deficiency (ID) is reported to inhibit the initiation of fear memory. In our study, we found that ferroportin1 (FPN1), the only known cellular iron export protein in mammals, and ablation in neurons and astrocytes caused iron deficiency in the cortex and hippocampus. However, little is known about its role in the development of fear memory. Moreover, direct evidence of the role of FPN1, or the related molecular mechanisms of such a role, in balancing brain iron homeostasis, especially in neuronal cells, is lacking. Herein, we deleted Fpn1 in mouse neurons, using Nestin-cre transgenic mice, and explored the impact on neuronal iron recycling and brain iron homeostasis in the cortex and hippocampus. We investigated the response of the mice to contextual fear and found that formation of fear memory was impeded after neuronal FPN1 depletion. We also found that FPN1 ablation in neurons and astrocytes caused an atypical expression of iron metabolism-related proteins in these two regions: decreased expression of DMT1, Ft-H, and Ft-L, and increased TfR1 expression. In addition, the decreased FPN1 in brain microvascular endothelial cells (BMVECs) also shed light on the cause of the decreased iron delivery to the brain through the blood-brain barrier (BBB). Our research highlights the major role played by FPN1 in brain iron homeostasis and identifies a potential target for the treatment of PTSD. K E Y W O R D Sbrain iron homeostasis, contextual fear, ferroportin1, Nestin-cre 2 of 15 | WU et al.

Cellular iron depletion enhances behavioral rhythm by limiting brain Per1 expression in mice

“…FPN1 is the only protein known to export cellular iron in mammals. 28 Conditional knockout of FPN1 in cerebral microvascular endothelial cells ( Fpn1 Cdh5 ‐cKO) inhibits the transport of peripheral iron into the brain through the blood–brain barrier (BBB), leading to brain iron deficiency. 20 FtH and FtL are cellular iron storage proteins that are usually used as indicators of uncommitted iron levels.…”

Single‐Vesicle Electrochemistry Following Repetitive Stimulation Reveals a Mechanism for Plasticity Changes with Iron Deficiency

“…Previous studies of brain iron homeostasis have highlighted the role of iron deficiency in memory formation. Knocking out the cellular iron export protein, ferroportin1, induces iron deficiency in neurons in cortex and hippocampus, which negatively affects the formation of fear memory and the contextual fear response in mice [34] . Iron deficiency in foetal and early postnatal life also affects brain growth and development.…”

“…Knocking out the cellular iron export protein, ferroportin1, induces iron deficiency in neurons in cortex and hippocampus, which negatively affects the formation of fear memory and the contextual fear response in mice. [34] Iron deficiency in foetal and early postnatal life also affects brain growth and development. For example, children with iron deficiency during early development have slower and smaller neurological and behavioural responses, despite subsequent treatment with adequate iron for 10 years.…”

Ccdc134 deficiency impairs cerebellar development and motor coordination

“…In addition, we also found incomplete knockout of Ccdc134 after crossing with Nestin-Cre mice. Other studies also showed that there were incomplete knockout of targeted molecules using Nestincre driver, such as TCTP and Fpn1, 40,41 suggesting that Nestin-cre driver targeting neural stem and progenitor cells, might lead to a significant decrease in the expression of targeted molecules in neuronal cells of cKO mice but not reach complete gene knockout.…”