Latent iron deficiency alters gamma-aminobutyric acid and glutamate metabolism in rat brain

Shukla, Arti; Agarwal, K. N.; Shukla, Girja S.

doi:10.1007/bf01957472

Cited by 22 publications

(10 citation statements)

References 23 publications

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“…These broader effects in the dietary model might have been due to the secondary effects of IDA rather than direct effects of ID. Our results are consistent with studies linking dietary ID after weaning with decreased brain glutamate concentrations (53,54). Iron levels regulate central nervous system glutamate formation and secretion via the iron-dependent enzyme cytosolic aconitase (IRP-1) in retinal pigment epithelial cells (55).…”

Section: Discussionsupporting

confidence: 93%

Iron Is Essential for Neuron Development and Memory Function in Mouse Hippocampus

Carlson

Tkáč

Magid

et al. 2009

The Journal of Nutrition

166

195

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Iron deficiency (ID) is the most prevalent micronutrient deficiency in the world and it affects neurobehavioral outcome. It is unclear whether the effect of dietary ID on the brain is due to the lack of neuronal iron or from other processes occurring in conjunction with ID (e.g. hypoxia due to anemia). We delineated the role of murine Slc11a2 [divalent metal ion transporter-1 (DMT-1)] in hippocampal neuronal iron uptake during development and memory formation. Camk2a gene promoter-driven cre recombinase (Cre) transgene (Camk2a-Cre) mice were mated with Slc11a2 flox/flox mice to obtain nonanemic Slc11a2(hipp/hipp) (double mutant, hippocampal neuron-specific knockout of Slc11a2(hipp/hipp)) mice, the first conditionally targeted model of iron uptake in the brain. Slc11a2(hipp/hipp) mice had lower hippocampal iron content; altered developmental expression of genes involved in iron homeostasis, energy metabolism, and dendrite morphogenesis; reductions in markers for energy metabolism and glutamatergic neurotransmission on magnetic resonance spectroscopy; and altered pyramidal neuron dendrite morphology in area 1 of Ammon's Horn in the hippocampus. Slc11a2(hipp/hipp) mice did not reach the criterion on a difficult spatial navigation test but were able to learn a spatial navigation task on an easier version of the Morris water maze (MWM). Learning of the visual cued task did not differ between the Slc11a2(WT/WT) and Slc11a2(hipp/hipp) mice. Slc11a2(WT/WT) mice had upregulation of genes involved in iron uptake and metabolism in response to MWM training, and Slc11a2(hipp/hipp) mice had differential expression of these genes compared with Slc11a2(WT/WT) mice. Neuronal iron uptake by DMT-1 is essential for normal hippocampal neuronal development and Slc11a2 expression is induced by spatial memory training. Deletion of Slc11a2 disrupts hippocampal neuronal development and spatial memory behavior.

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Section: Discussionsupporting

confidence: 93%

Iron Is Essential for Neuron Development and Memory Function in Mouse Hippocampus

Carlson

Tkáč

Magid

et al. 2009

The Journal of Nutrition

166

195

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“…Lozoff et al found that children with severe, chronic ID in infancy had a greater prevalence of anxiety, depression, and attention problems [40]. Some animal studies have shown an association between IDA and alterations in serotonin, norepinephrine, and gamma-aminobutyric acid (GABA) neurotransmission [21,61]. In assessing weanling rats with either an iron deficient diet or a control diet for 6 weeks, Beard et al found reduced activity and increased anxiety-like behaviors among the iron deficient rats with significant decrements in brain iron content in the corpus striatum, prefrontal cortex, and midbrain [62].…”

Section: Discussionmentioning

confidence: 99%

Association between psychiatric disorders and iron deficiency anemia among children and adolescents: a nationwide population-based study

et al. 2013

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BackgroundA great deal of evidence has shown that iron is an important component in cognitive, sensorimotor, and social-emotional development and functioning, because the development of central nervous system processes is highly dependent on iron-containing enzymes and proteins. Deficiency of iron in early life may increase the risk of psychiatric morbidity.MethodsUtilizing the National Health Insurance Database from 1996 to 2008, children and adolescents with a diagnosis of IDA were identified and compared with age and gender-matched controls (1:4) in an investigation of the increased risk of psychiatric disorders.ResultsA total of 2957 patients with IDA, with an increased risk of unipolar depressive disorder (OR = 2.34, 95% CI = 1.58 ~ 3.46), bipolar disorder (OR = 5.78, 95% CI = 2.23 ~ 15.05), anxiety disorder (OR = 2.17, 95% CI = 1.49 ~ 3.16), autism spectrum disorder (OR = 3.08, 95% CI = 1.79 ~ 5.28), attention deficit hyperactivity disorder (OR = 1.67, 95% CI = 1.29 ~ 2.17), tic disorder (OR = 1.70, 95% CI = 1.03 ~ 2.78), developmental delay (OR = 2.45, 95% CI = 2.00 ~ 3.00), and mental retardation (OR = 2.70, 95% CI = 2.00 ~ 3.65), were identified. A gender effect was noted, in that only female patients with IDA had an increased OR of bipolar disorder (OR = 5.56, 95% CI = 1.98 ~ 15.70) and tic disorder (OR = 2.95, 95% CI = 1.27 ~ 6.86).ConclusionIron deficiency increased the risk of psychiatric disorders, including mood disorders, autism spectrum disorder, attention deficit hyperactivity disorder, and developmental disorders. Further study is required to clarify the mechanism in the association between IDA and psychiatric disorder.

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“…An inverse correlation between extracellular GABA and Fe concentrations was also observed, with GABA concentration increasing with decreased Fe, suggesting that decreased Fe (due to both dietary deficiency and Mn-exposure) affects the levels of extracellular GABA. Iron deficiency affects GABA synthesis via glutamate decarboxylase (GAD) (Li, 1998) and a reduction in GABA brain tissue concentrations has been shown in rats fed a marginally ID diet for eight weeks (Shukla et al, 1989). Low tissue neurotransmitter levels may be the result of decreased uptake of the respective neurotransmitter (Gainetdinov et al, 1998), increasing the extracellular concentrations, a scenario which might be occurring in the current study.…”

Section: Discussionmentioning

confidence: 99%

Manganese exposure alters extracellular GABA, GABA receptor and transporter protein and mRNA levels in the developing rat brain

et al. 2008

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Unlike other essential trace elements (e.g., zinc and iron) it is the toxicity of manganese (Mn) that is more common in human populations than its deficiency. Data suggest alterations in dopamine biology may drive the effects associated with Mn neurotoxicity, though recently γ-aminobutyric acid (GABA) has been implicated. In addition, iron deficiency (ID), a common nutritional problem, may cause disturbances in neurochemistry by facilitating accumulation of Mn in the brain. Previous data from our lab have shown decreased brain tissue levels of GABA as well as decreased 3H-GABA uptake in synaptosomes as a result of Mn exposure and ID. These results indicate a possible increase in the concentration of extracellular GABA due to alterations in expression of GABA transport and receptor proteins. In this study weanling-male Sprague-Dawley rats were randomly placed into one of four dietary treatment groups: control (CN; 35 mg Fe/kg diet), iron-deficient (ID; 6 mg Fe/kg diet), CN with Mn supplementation (via the drinking water; 1 g Mn/L) (CNMn), and ID with Mn supplementation (IDMn). Using in vivo microdialysis, an increase in extracellular GABA concentrations in the striatum was observed in response to Mn exposure and ID although correlational analysis reveals that extracellular GABA is related more to extracellular iron levels and not Mn. A diverse effect of Mn exposure and ID was observed in the regions examined via Western blot and RT-PCR analysis, with effects on mRNA and protein expression of GAT-1, GABAA, and GABAB differing between and within the regions examined. For example, Mn exposure reduced GAT-1 protein expression by approximately 50% in the substantia nigra, while increasing mRNA expression approximately four-fold, while in the caudate putamen mRNA expression was decreased with no effect on protein expression. These data suggest that Mn exposure results in an increase in extracellular GABA concentrations via altered expression of transport and receptor proteins, which may be the basis of the neurological characteristics of manganism.

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Latent iron deficiency alters gamma-aminobutyric acid and glutamate metabolism in rat brain

Abstract: A diet containing 18-20 mg iron/kg to young weaned rats for 8 weeks altered the metabolism of gamma-aminobutyric acid and glutamate in the central nervous system without affecting blood hemoglobin. Subsequent rehabilitation with 390 mg iron/kg diet for 2 weeks normalized these changes.

Cited by 22 publications

References 23 publications

Iron Is Essential for Neuron Development and Memory Function in Mouse Hippocampus

Iron Is Essential for Neuron Development and Memory Function in Mouse Hippocampus

Association between psychiatric disorders and iron deficiency anemia among children and adolescents: a nationwide population-based study

Manganese exposure alters extracellular GABA, GABA receptor and transporter protein and mRNA levels in the developing rat brain

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