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Fetal Iron Deficiency Alters The Proteome Of Adult Rat Hippocampal Synaptosomes.

Phu V. Tran, Srikanth Dakoji, Kathryn Reise, Kathleen K. Storey, Michael K. Georgieff
Published 2013 · Medicine, Biology
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Fetal and neonatal iron deficiency results in cognitive impairments in adulthood despite prompt postnatal iron replenishment. To systematically determine whether abnormal expression and localization of proteins that regulate adult synaptic efficacy are involved, we used a quantitative proteomic approach (isobaric tags for relative and absolute quantitation, iTRAQ) and pathway analysis to identify dysregulated proteins in hippocampal synapses of fetal iron deficiency model. Rat pups were made iron deficient (ID) from gestational day 2 through postnatal day (P) 7 by providing pregnant and nursing dams an ID diet (4 ppm Fe) after which they were rescued with an iron-sufficient diet (200 ppm Fe). This paradigm resulted in a 40% loss of brain iron at P15 with complete recovery by P56. Synaptosomes were prepared from hippocampi of the formerly iron-deficient (FID) and always iron-sufficient controls rats at P65 using a sucrose gradient method. Six replicates per group that underwent iTRAQ labeling and LC-MS/MS analysis for protein identification and comparison elucidated 331 differentially expressed proteins. Western analysis was used to confirm findings for selected proteins in the glutamate receptor signaling pathway, which regulates hippocampal synaptic plasticity, a cellular process critical for learning and memory. Bioinformatics were performed using knowledge-based Interactive Pathway Analysis. FID synaptosomes show altered expression of synaptic proteins-mediated cellular signalings, supporting persistent impacts of fetal iron deficiency on synaptic efficacy, which likely cause the cognitive dysfunction and neurobehavioral abnormalities. Importantly, the findings uncover previously unsuspected pathways, including neuronal nitric oxide synthase signaling, identifying additional mechanisms that may contribute to the long-term biobehavioral deficits.
This paper references
10.1074/jbc.M109.026237
Interaction of Akt-phosphorylated SRPK2 with 14-3-3 Mediates Cell Cycle and Cell Death in Neurons*
Sung-Wuk Jang (2009)
10.1074/mcp.T600050-MCP200
The Paragon Algorithm, a Next Generation Search Engine That Uses Sequence Temperature Values and Feature Probabilities to Identify Peptides from Tandem Mass Spectra*S
Ignat V Shilov (2007)
10.1093/jpepsy/jsp065
Longitudinal evaluation of externalizing and internalizing behavior problems following iron deficiency in infancy.
Feyza Çorapçi (2010)
10.1203/01.pdr.0000127021.38207.62
Iron Deficiency Alters Auditory Recognition Memory in Newborn Infants of Diabetic Mothers
Ashajyothi M Siddappa (2004)
10.1586/epr.12.15
High-pH reversed-phase chromatography with fraction concatenation for 2D proteomic analysis
Feng Yang (2012)
10.1074/mcp.M111.008110
Proteomic and Metabolomic Profiling of a Trait Anxiety Mouse Model Implicate Affected Pathways*
Yaoyang Zhang (2011)
10.1542/peds.2008-3007
Effects of Maternal Multimicronutrient Supplementation on the Mental Development of Infants in Rural Western China: Follow-up Evaluation of a Double-Blind, Randomized, Controlled Trial
Qiang Li Li (2009)
10.1159/000073507
Pre- and Postweaning Iron Deficiency Alters Myelination in Sprague-Dawley Rats
John L. Beard (2003)
10.3945/jn.108.096354
Iron is essential for neuron development and memory function in mouse hippocampus.
Erik S. Carlson (2009)
10.1179/147683010X12611460763689
Iron deficiency in infancy and neurocognitive functioning at 19 years: evidence of long-term deficits in executive function and recognition memory
Angela F Lukowski (2010)
10.3945/jn.112.162198
Behavior and monoamine deficits in prenatal and perinatal iron deficiency are not corrected by early postnatal moderate-iron or high-iron diets in rats.
Erica L. Unger (2012)
10.3945/jn.108.091553
Early-life iron deficiency anemia alters neurotrophic factor expression and hippocampal neuron differentiation in male rats.
Phu V. Tran (2008)
10.1002/hipo.20307
Perinatal iron deficiency results in altered developmental expression of genes mediating energy metabolism and neuronal morphogenesis in hippocampus.
Erik S. Carlson (2007)
10.1016/j.brainres.2008.08.079
Effects of gestational iron deficiency on fear conditioning in juvenile and adult rats
Jonathan C. Gewirtz (2008)
10.1136/fn.84.1.F40
Study of maternal influences on fetal iron status at term using cord blood transferrin receptors
David G. Sweet (2001)
10.1196/annals.1300.001
Synaptic plasticity and AMPA receptor trafficking.
Robert C. Malenka (2003)
10.1093/jn/133.4.1174
Neonatal iron deficiency results in irreversible changes in dopamine function in rats.
John L. Beard (2003)
10.1016/0361-9230(81)90075-7
Postnatal ontogenesis of hippocampal CA1 area in rats. I. Development of dendritic arborisation in pyramidal neurons
Jan Pokorný (1981)
10.1074/mcp.M900435-MCP200
Global Phosphoproteomics Identifies a Major Role for AKT and 14-3-3 in Regulating EDC3*
Mark Larance (2010)
10.1067/mpd.2002.127090
Iron status at 9 months of infants with low iron stores at birth.
Michael K. Georgieff (2002)
10.1021/pr070086w
Quantitative proteomics and protein network analysis of hippocampal synapses of CaMKIIalpha mutant mice.
Ka Wan Li (2007)
10.1016/j.siny.2006.10.007
Iron in fetal and neonatal nutrition.
Raghavendra B Rao (2007)
10.1079/BJN20031043
Mental and psychomotor development in Indonesian infants of mothers supplemented with vitamin A in addition to iron during pregnancy.
Marjanka K. Schmidt (2004)
10.1007/978-3-211-33328-0_19
Acute and chronic effects of developmental iron deficiency on mRNA expression patterns in the brain.
Stacey Lynn Clardy (2006)
10.1111/j.1471-4159.1988.tb03027.x
Selective alteration in blood-brain barrier and insulin transport in iron-deficient rats.
Dorit Ben-Shachar (1988)
10.1016/j.neuropharm.2010.12.012
Synaptoproteomics of learned helpless rats involve energy metabolism and cellular remodeling pathways in depressive-like behavior and antidepressant response
Alessandra Mallei (2011)
10.1016/j.neuint.2007.09.015
Proposed cycles for functional glutamate trafficking in synaptic neurotransmission
Paul K. Maciejewski (2008)
10.1016/S1097-2765(05)00012-2
14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation.
Sandeep Robert Datta (2000)
10.1016/S0016-5085(00)86380-5
Iron deficiency suppresses ileal nitric oxide synthase activity
Matthew I. Goldblatt (2000)
Relationship of iron to oligodendrocytes and myelination.
J R Connor (1996)
10.1159/000075667
Perinatal Iron Deficiency Alters Apical Dendritic Growth in Hippocampal CA1 Pyramidal Neurons
Lyric A. Jorgenson (2003)
10.1038/pr.2012.143
Iron supplementation dose for perinatal iron deficiency differentially alters the neurochemistry of the frontal cortex and hippocampus in adult rats
Raghavendra Desai Rao (2013)
10.1152/ajpregu.1992.262.3.R485
Fetal iron and cytochrome c status after intrauterine hypoxemia and erythropoietin administration.
Michael K. Georgieff (1992)
10.1159/000341919
Quantitative Proteomic Analyses of Cerebrospinal Fluid Using iTRAQ in a Primate Model of Iron Deficiency Anemia
Stephanie M. Patton (2012)
10.1074/jbc.M110.213785
Iron Mediates N-Methyl-d-aspartate Receptor-dependent Stimulation of Calcium-induced Pathways and Hippocampal Synaptic Plasticity*
Pablo Muñoz (2011)
10.1002/hipo.20128
Fetal iron deficiency disrupts the maturation of synaptic function and efficacy in area CA1 of the developing rat hippocampus.
Lyric A. Jorgenson (2005)
10.1016/S0022-3476(05)82554-5
Iron deficiency of liver, heart, and brain in newborn infants of diabetic mothers.
C D Petry (1992)
10.1073/pnas.95.1.316
Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity.
Nicola R. Sibson (1998)
10.1152/ajpendo.00369.2011
Gestational-neonatal iron deficiency suppresses and iron treatment reactivates IGF signaling in developing rat hippocampus.
Phu V. Tran (2012)
10.1523/JNEUROSCI.3795-04.2004
Different Presynaptic Roles of Synapsins at Excitatory and Inhibitory Synapses
Daniel Gitler (2004)
10.1037/0735-7044.121.3.475
Dissociating the long-term effects of fetal/neonatal iron deficiency on three types of learning in the rat.
Adam T. Schmidt (2007)
10.1038/ki.1997.319
Up-regulation of renal and vascular nitric oxide synthase in iron-deficiency anemia.
Zhenmin Ni (1997)
10.1002/hipo.22151
Iron deficiency with or without anemia impairs prepulse inhibition of the startle reflex.
Marc T Pisansky (2013)
10.1159/000100805
The Assessment of Newborn Iron Stores at Birth: A Review of the Literature and Standards for Ferritin Concentrations
Ashajyothi M Siddappa (2007)
10.1002/(SICI)1098-1136(199606)17:2<83::AID-GLIA1>3.0.CO;2-7
Relationship of iron to oligondendrocytes and myelination
James R. Connor (1996)
10.1162/089976698300017908
The Role of the Hippocampus in Solving the Morris Water Maze
A. David Redish (1998)
10.1016/j.neuron.2006.07.011
NMDA Receptor-Nitric Oxide Transmission Mediates Neuronal Iron Homeostasis via the GTPase Dexras1
Jaime H. Cheah (2006)
10.1210/en.2010-0252
Perinatal iron and copper deficiencies alter neonatal rat circulating and brain thyroid hormone concentrations.
Thomas W. Bastian (2010)
10.1074/jbc.M112.405761
Re-evaluation of the Role of Calcium Homeostasis Endoplasmic Reticulum Protein (CHERP) in Cellular Calcium Signaling*
Yaping Lin-Moshier (2012)
10.1042/bj1230211
A simulation study of brain compartments. Metabolism of glutamate and related substances in mouse brain.
C J van den Berg (1971)
10.1179/1476830511Y.0000000001
Fetal and neonatal iron deficiency causes volume loss and alters the neurochemical profile of the adult rat hippocampus
Raghu Rao (2011)
10.1016/S0022-3476(87)80088-4
Cord transferrin and ferritin values in newborn infants at risk for prenatal uteroplacental insufficiency and chronic hypoxia.
U M Chockalingam (1987)
10.1007/s00213-008-1072-4
Realistic expectations of prepulse inhibition in translational models for schizophrenia research
Neal R. Swerdlow (2008)
10.1016/S0166-2236(02)02241-5
Stressed-out, or in (utero)?
Sarit Avishai-Eliner (2002)
10.1111/j.1468-1331.2011.03397.x
Hypoxia-inducible factor pathway activation in restless legs syndrome patients.
Stephanie M. Patton (2011)
10.1093/jn/133.10.3215
Perinatal iron deficiency alters the neurochemical profile of the developing rat hippocampus.
Raghavendra B Rao (2003)
10.1159/000314341
Gestational and Neonatal Iron Deficiency Alters Apical Dendrite Structure of CA1 Pyramidal Neurons in Adult Rat Hippocampus
Katyarina E. Brunette (2010)
10.1098/rstb.2002.1233
AMPA receptor trafficking and long-term potentiation.
Roberto Malinow (2003)
10.1016/j.bbr.2006.04.001
Persistent neurochemical and behavioral abnormalities in adulthood despite early iron supplementation for perinatal iron deficiency anemia in rats
Barbara T. Felt (2006)
10.1542/peds.2011-3513
Effect of Iron Deficiency Anemia in Pregnancy on Child Mental Development in Rural China
Suying Chang (2013)
10.1523/jneurosci.06-02-00563.1986
Long-term enhancement of hippocampal synaptic transmission and the acquisition of spatial information
Bruce L. McNaughton (1986)
10.1093/ajcn/85.4.931
An overview of evidence for a causal relation between iron deficiency during development and deficits in cognitive or behavioral function.
Joyce C. McCann (2007)
10.1073/pnas.93.26.15451
Ca2+/calmodulin-dependent protein kinase II phosphorylation of the presynaptic protein synapsin I is persistently increased during long-term potentiation.
Abinash Nayak (1996)
10.1016/S0092-8674(00)81053-3
Interaction of Nitric Oxide Synthase with the Postsynaptic Density Protein PSD-95 and α1-Syntrophin Mediated by PDZ Domains
Jay E. Brenman (1996)
10.1093/jn/137.3.683
Preschool-aged children with iron deficiency anemia show altered affect and behavior.
Betsy Lozoff (2007)
10.1203/PDR.0b013e31819d90a1
Long-Term Reduction of Hippocampal Brain-Derived Neurotrophic Factor Activity After Fetal-Neonatal Iron Deficiency in Adult Rats
Phu V. Tran (2009)
10.1016/j.neuron.2005.01.039
Generation of Silent Synapses by Acute In Vivo Expression of CaMKIV and CREB
Hélène Marie (2005)
10.1615/CritRevNeurobiol.v18.i1-2.80
Hippocampal long-term synaptic plasticity and signal amplification of NMDA receptors.
John F. Macdonald (2006)
10.1038/nature11775
LTP requires a reserve pool of glutamate receptors independent of subunit type
Adam J. Granger (2013)
10.1301/nr.2006.may.S34-S43
Long-lasting neural and behavioral effects of iron deficiency in infancy.
Betsy Lozoff (2006)
10.1523/JNEUROSCI.1497-12.2013
Dexras1, a Small GTPase, Is Required for Glutamate-NMDA Neurotoxicity
Yong Chen (2013)
10.1083/jcb.86.3.831
Isolation and characterization of postsynaptic densities from various brain regions: enrichment of different types of postsynaptic densities
R K Carlin (1980)
10.1001/archpsyc.65.10.1136
Maternal iron deficiency and the risk of schizophrenia in offspring.
Beverly J. Insel (2008)
10.1046/j.1471-4159.1995.64031298.x
Protein kinase C modulates calcium sensitivity of nitric oxide synthase in cerebellar slices.
Daisuke Okada (1995)
10.1001/jama.2010.1861
Prenatal micronutrient supplementation and intellectual and motor function in early school-aged children in Nepal.
Parul Christian (2010)



This paper is referenced by
10.1017/S0954579418000500
Atypical fetal development: Fetal alcohol syndrome, nutritional deprivation, teratogens, and risk for neurodevelopmental disorders and psychopathology.
Michael K. Georgieff (2018)
10.1177/2633105520935104
The Effects of Early-Life Iron Deficiency on Brain Energy Metabolism
Thomas W. Bastian (2020)
10.1371/journal.pone.0142630
Helicobacter pylori Infection Induces Anemia, Depletes Serum Iron Storage, and Alters Local Iron-Related and Adult Brain Gene Expression in Male INS-GAS Mice
Monika A Burns (2015)
10.1111/mmi.12768
Proteomic profiling of a robust Wolbachia infection in an Aedes albopictus mosquito cell line.
Gerald D. Baldridge (2014)
10.1111/1471-0528.14263
The effect of maternal haematocrit on offspring IQ at 4 and 7 years of age: a secondary analysis.
Daphnie Drassinower (2016)
10.1002/9781119125556.DEVPSY206
The Role of Early Nutritional Deficiencies in the Development of Psychopathology
Adam T. Schmidt (2016)
10.1080/1028415x.2020.1740862
Iron-deficient diet induces distinct protein profile related to energy metabolism in the striatum and hippocampus of adult rats.
Jessica Monteiro Volejnik Pino (2020)
10.1097/DBP.0000000000000203
Functional and Anatomic Consequences of Diabetic Pregnancy on Memory in Ten-Year-Old Children
Adeline Jabès (2015)
10.3945/jn.115.227561
Prenatal Choline Supplementation Diminishes Early-Life Iron Deficiency-Induced Reprogramming of Molecular Networks Associated with Behavioral Abnormalities in the Adult Rat Hippocampus.
Phu V. Tran (2016)
10.1093/jn/nxz100
Early-Life Iron Deficiency Alters Glucose Transporter-1 Expression in the Adult Rodent Hippocampus.
Kathleen M. Ennis (2019)
10.21776/ub.jkb.2020.031.01.12
Iron Status of Newborns and Umbilical Cord Blood Hepcidin Levels in Gender Differences
Qodri Santosa (2020)
10.1017/S0007114517002410
The impacts of maternal iron deficiency and being overweight during pregnancy on neurodevelopment of the offspring.
Staffan K. Berglund (2017)
10.1091/mbc.E16-03-0191
The role of the dynein light intermediate chain in retrograde IFT and flagellar function in Chlamydomonas
Jaimee Reck (2016)
10.3945/jn.116.241364
Evidence Favoring a Positive Feedback Loop for Physiologic Auto Upregulation of hnRNP-E1 during Prolonged Folate Deficiency in Human Placental Cells.
Ying-Sheng Tang (2017)
10.1159/000499126
Perinatal Ischemia Alters Global Expression of Synaptosomal Proteins Critical for Neural Plasticity in the Developing Mouse Brain
Amanda K Barks (2018)
10.1016/j.bbr.2017.04.009
Maternal hypomagnesemia alters hippocampal NMDAR subunit expression and programs anxiety-like behaviour in adult offspring
R. N. Schlegel (2017)
10.1152/ajpregu.00429.2014
Fetal iron deficiency induces chromatin remodeling at the Bdnf locus in adult rat hippocampus.
Phu V. Tran (2015)
10.1371/journal.pone.0165980
Glucose Starvation Alters Heat Shock Response, Leading to Death of Wild Type Cells and Survival of MAP Kinase Signaling Mutant
Nora Plesofsky (2016)
10.1007/s12098-015-1904-2
Fetal Effects of Maternal Iron Deficiency
Deepak Chawla (2015)
10.1038/jp.2016.234
The iron status at birth of neonates with risk factors for developing iron deficiency: a pilot study
Brianna C Macqueen (2017)
10.1038/s41598-019-44140-3
Association between APOE4 and biomarkers in cerebral adrenoleukodystrophy
Paul J Orchard (2019)
10.1002/pmic.201600407
The Effects of Prenatal Iron Deficiency and Risperidone Treatment on the Rat Frontal Cortex:  A Proteomic Analysis.
Lorna A. Farrelly (2017)
10.3390/nu11102478
Cord Blood-Derived Exosomal CNTN2 and BDNF: Potential Molecular Markers for Brain Health of Neonates at Risk for Iron Deficiency
Paulina S Marell (2019)
10.1016/B978-0-323-40139-5.00081-4
Neonatal Erythrocyte Disorders
Robert D. Christensen (2018)
10.1016/S0016-5085(15)31761-3
Su1825 Helicobacter pylori Infection Induces Anemia, Depletes Serum Iron Storage, and Alters Local Iron-Related and Adult Brain Gene Expression in Male INS-GAS Mice
Monika A Burns (2015)
10.1007/s40124-014-0058-4
Striking While the Iron is Hot: Understanding the Biological and Neurodevelopmental Effects of Iron Deficiency to Optimize Intervention in Early Childhood
Jenalee R Doom (2014)
10.1152/ajpregu.00066.2016
Deletion of novel protein TMEM35 alters stress-related functions and impairs long-term memory in mice.
Bruce C. Kennedy (2016)
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