Iron Deficiency Impairs Developing Hippocampal Neuron Gene Expression, Energy Metabolism, and Dendrite Complexity.
Iron deficiency (ID), with and without anemia, affects an estimated 2 billion people worldwide. ID is particularly deleterious during early-life brain development, leading to long-term neurological impairments including deficits in hippocampus-mediated learning and memory. Neonatal rats with fetal/neonatal ID anemia (IDA) have shorter hippocampal CA1 apical dendrites with disorganized branching. ID-induced dendritic structural abnormalities persist into adulthood despite normalization of the iron status. However, the specific developmental effects of neuronal iron loss on hippocampal neuron dendrite growth and branching are unknown. Embryonic hippocampal neuron cultures were chronically treated with deferoxamine (DFO, an iron chelator) beginning at 3 days in vitro (DIV). Levels of mRNA for Tfr1 and Slc11a2, iron-responsive genes involved in iron uptake, were significantly elevated in DFO-treated cultures at 11DIV and 18DIV, indicating a degree of neuronal ID similar to that seen in rodent ID models. DFO treatment decreased mRNA levels for genes indexing dendritic and synaptic development (i.e. BdnfVI,Camk2a,Vamp1,Psd95,Cfl1, Pfn1,Pfn2, and Gda) and mitochondrial function (i.e. Ucp2,Pink1, and Cox6a1). At 18DIV, DFO reduced key aspects of energy metabolism including basal respiration, maximal respiration, spare respiratory capacity, ATP production, and glycolytic rate, capacity, and reserve. Sholl analysis revealed a significant decrease in distal dendritic complexity in DFO-treated neurons at both 11DIV and 18DIV. At 11DIV, the length of primary dendrites and the number and length of branches in DFO-treated neurons were reduced. By 18DIV, partial recovery of the dendritic branch number in DFO-treated neurons was counteracted by a significant reduction in the number and length of primary dendrites and the length of branches. Our findings suggest that early neuronal iron loss, at least partially driven through altered mitochondrial function and neuronal energy metabolism, is responsible for the effects of fetal/neonatal ID and IDA on hippocampal neuron dendritic and synaptic maturation. Impairments in these neurodevelopmental processes likely underlie the negative impact of early life ID and IDA on hippocampus-mediated learning and memory.
Department of Pediatrics and Center for Neurobehavioral Development, School of Medicine, Minneapolis, Minn., USA.
Thomas W
TW
Bastian
William C
WC
von Hohenberg
Daniel J
DJ
Mickelson
Lorene M
LM
Lanier
Michael K
MK
Georgieff
D018798:Anemia, Iron-Deficiency / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D003712:Dendrites / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology*; D015870:Gene Expression / Q000502:physiology*; D006624:Hippocampus / Q000254:growth & development* / Q000378:metabolism*; D000090463:Iron Deficiencies; D007858:Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D055495:Neurogenesis
Annu Rev Nutr. 1986;6:13-40
3524613
Dev Neurosci. 2010 Aug;32(3):238-48
20689287
J Neurosci. 1994 Nov;14(11 Pt 1):6402-11
7965045
Science. 1998 Jan 9;279(5348):222-6
9422694
J Nutr. 2009 Apr;139(4):672-9
19211831
Oxid Med Cell Longev. 2013;2013:601587
23533695
J Nutr. 1994 Aug;124(8 Suppl):1479S-1490S
8064407
Pediatr Res. 2016 Mar;79(3):482-8
26599151
J Nutr. 2003 Oct;133(10):3215-21
14519813
Pediatr Res. 2004 Jun;55(6):1034-41
15155871
Am J Clin Nutr. 2011 Jun;93(6):1312-20
21430118
Biochem J. 2010 May 27;428(3):363-74
20307258
Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15780-5
20798032
J Neurosci. 2015 Apr 8;35(14):5707-23
25855183
Med Res Rev. 2002 Jan;22(1):26-64
11746175
J Neurosci. 1997 Aug 15;17(16):6314-24
9236241
Front Cell Neurosci. 2015 Jul 20;9:269
26257605
Nutr Neurosci. 2011 Mar;14 (2):59-65
21605501
Dev Neurosci. 2003 Nov-Dec;25(6):412-20
14966382
J Neurosci Methods. 2007 Apr 15;161(2):281-4
17184842
J Nutr. 2005 May;135(5):1002-7
15867272
Nat Methods. 2012 Jul;9(7):671-5
22930834
J Neurosci Res. 2002 Jun 15;68(6):761-75
12111837
Hippocampus. 2013 Oct;23(10):952-62
23733517
Nat Rev Neurosci. 2013 Aug;14(8):536-50
23839597
Brain Res Dev Brain Res. 1990 Aug 1;55(1):35-42
2208639
Public Health Nutr. 2009 Apr;12(4):444-54
18498676
J Nutr. 2008 Dec;138(12):2495-501
19022978
Nat Neurosci. 2004 Feb;7(2):145-52
14730308
Behav Brain Res. 2006 Aug 10;171(2):261-70
16713640
Hippocampus. 2005;15(8):1094-102
16187331
Genes Dev. 2012 Aug 1;26(15):1743-57
22810622
Cell. 2010 Jul 9;142(1):24-38
20603012
Pediatr Res. 2000 Aug;48(2):169-76
10926291
J Nutr. 2014 Jul;144(7):1058-66
24744313
Cell Metab. 2005 Aug;2(2):85-93
16098826
Annu Rev Neurosci. 2007;30:399-423
17378766
Adv Nutr. 2011 Mar;2(2):112-21
22332040
Nat Methods. 2012 Jun 28;9(7):676-82
22743772
Cytometry A. 2009 Apr;75(4):371-6
18937344
Brain Res Bull. 1981 Aug;7(2):113-20
7272792
Neurobiol Learn Mem. 2004 Nov;82(3):171-7
15464402
J Virol. 1996 Jul;70(7):4646-54
8676491
J Nutr. 2014 Nov;144(11):1858-65
25332485
Cell Metab. 2012 Dec 5;16(6):789-800
23217258
J Cell Biol. 2014 Mar 31;204(7):1087-98
24687278
Cell. 1994 Apr 8;77(1):1-3
8156586
Cereb Cortex. 2000 Oct;10(10):963-73
11007547
Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14670-5
19667196
Hippocampus. 2012 Aug;22(8):1691-702
22367974
J Neurophysiol. 2014 Sep 15;112(6):1559-65
24944211
J Anat. 1953 Oct;87(4):387-406
13117757
Neuron. 2004 Jul 8;43(1):81-94
15233919
Hippocampus. 2007;17(8):679-91
17546681
J Pediatr. 1992 Jul;121(1):109-14
1625067
J Biol Chem. 2015 Dec 4;290(49):29603-16
26475861
Am J Clin Nutr. 2009 May;89(5):1334-42
19357218
Science. 2000 Nov 17;290(5495):1364-8
11082065
Nat Protoc. 2006;1(5):2406-15
17406484