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Transferrin Receptor 2 Dependent Alterations of Brain Iron Metabolism Affect Anxiety Circuits in the Mouse.

ABSTRACT: The Transferrin Receptor 2 (Tfr2) modulates systemic iron metabolism through the regulation of iron regulator Hepcidin (Hepc) and Tfr2 inactivation causes systemic iron overload. Based on data demonstrating Tfr2 expression in brain, we analysed Tfr2-KO mice in order to examine the molecular, histological and behavioural consequences of Tfr2 silencing in this tissue. Tfr2 abrogation caused an accumulation of iron in specific districts in the nervous tissue that was not accompanied by a brain Hepc response. Moreover, Tfr2-KO mice presented a selective overactivation of neurons in the limbic circuit and the emergence of an anxious-like behaviour. Furthermore, microglial cells showed a particular sensitivity to iron perturbation. We conclude that Tfr2 is a key regulator of brain iron homeostasis and propose a role for Tfr2 alpha in the regulation of anxiety circuits.

SUBMITTER: Pellegrino RM

PROVIDER: S-EPMC4967901 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Transferrin Receptor 2 Dependent Alterations of Brain Iron Metabolism Affect Anxiety Circuits in the Mouse.

Pellegrino Rosa Maria RM Boda Enrica E Montarolo Francesca F Boero Martina M Mezzanotte Mariarosa M Saglio Giuseppe G Buffo Annalisa A Roetto Antonella A

Scientific reports 20160801

The Transferrin Receptor 2 (Tfr2) modulates systemic iron metabolism through the regulation of iron regulator Hepcidin (Hepc) and Tfr2 inactivation causes systemic iron overload. Based on data demonstrating Tfr2 expression in brain, we analysed Tfr2-KO mice in order to examine the molecular, histological and behavioural consequences of Tfr2 silencing in this tissue. Tfr2 abrogation caused an accumulation of iron in specific districts in the nervous tissue that was not accompanied by a brain Hepc ...[more]

PMID: 27477597

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Project description:Mood disorders such as anxiety and depression are heterogeneous disorders with many sufferers unresponsive to current pharmacological treatments. Individual differences in temperament represent one factor that may underlie symptom heterogeneity, so understanding its biological underpinnings can help pave the way to personalized therapies and improved patient outcomes. The present study uses a rodent model of temperamental differences to examine whether individual differences in emotional behavior phenotypes correspond to altered limbic brain cellular metabolism, an indicator of neuronal activity. The model uses two selectively bred rat lines - high novelty responder rats (HRs) that show highly exploratory behavior in a novel environment, active coping style and resilience to chronic mild stress compared to low novelty responder rats (LRs), which are inhibited in novel environments, display passive coping style, and are susceptible to chronic stress. Utilizing transcriptome data from a prior study in adult HR/LR rats, we first show that a preponderance of genes differing in the HR vs. LR hippocampus and amygdala are involved in cellular metabolism. This led us to then ask if oxygen consumption was altered in isolated mitochondria of the hippocampus and amygdala of HR/LR rats; here we found increased oxygen consumption reserve capacity in LR amygdala. Our last experiment examined activity of cytochrome c oxidase (COX), an enzyme responsible for ATP production and correlate of metabolic activity, in several brain regions of HR/LR rats. We found that LRs displayed higher COX activity in the dentate gyrus, prefrontal cortex, and dorsal raphe compared to HRs, with no significant HR/LR difference in nuclei of the amygdala. Correlational analyses of COX activity across brain regions suggested divergent connectivity between the prefrontal cortex, amygdala, hippocampus, and dorsal raphe of HR vs. LR rats. Together these studies point to altered cellular metabolism in the limbic brain of LR/HR animals, which may reflect altered neural circuitry that drives their divergent behavioral profiles.

Project description:Iron is a necessary substrate for neuronal function throughout the lifespan, but particularly during development. Early life iron deficiency (ID) in humans (late gestation through 2-3 yr) results in persistent cognitive and behavioral abnormalities despite iron repletion. Animal models of early life ID generated using maternal dietary iron restriction also demonstrate persistent learning and memory deficits, suggesting a critical requirement for iron during hippocampal development. Precise definition of the temporal window for this requirement has been elusive due to anemia and total body and brain ID inherent to previous dietary restriction models. To circumvent these confounds, we developed transgenic mice that express tetracycline transactivator regulated, dominant negative transferrin receptor (DNTfR1) in hippocampal neurons, disrupting TfR1 mediated iron uptake specifically in CA1 pyramidal neurons. Normal iron status was restored by doxycycline administration. We manipulated the duration of ID using this inducible model to examine long-term effects of early ID on Morris water maze learning, CA1 apical dendrite structure, and defining factors of critical periods including parvalbmin (PV) expression, perineuronal nets (PNN), and brain-derived neurotrophic factor (BDNF) expression. Ongoing ID impaired spatial memory and resulted in disorganized apical dendrite structure accompanied by altered PV and PNN expression and reduced BDNF levels. Iron repletion at P21, near the end of hippocampal dendritogenesis, restored spatial memory, dendrite structure, and critical period markers in adult mice. However, mice that remained hippocampally iron deficient until P42 continued to have spatial memory deficits, impaired CA1 apical dendrite structure, and persistent alterations in PV and PNN expression and reduced BDNF despite iron repletion. Together, these findings demonstrate that hippocampal iron availability is necessary between P21 and P42 for development of normal spatial learning and memory, and that these effects may reflect disruption of critical period closure by early life ID.

Dataset Information

Transferrin Receptor 2 Dependent Alterations of Brain Iron Metabolism Affect Anxiety Circuits in the Mouse.

Publications

Transferrin Receptor 2 Dependent Alterations of Brain Iron Metabolism Affect Anxiety Circuits in the Mouse.

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