Genetic analysis reveals polygenic influences on iron, copper, and zinc in mouse hippocampus with neurobiological implications

Abstract

Fe, Cu, and Zn are of widespread neurobiological importance, but must be regulated closely as too much or too little of these metals can have adverse effects on brain function. Recent evidence from nutritional models notes that the hippocampus is particularly vulnerable to Fe and Zn deficiencies. We recently performed a quantitative trait loci (QTL) analysis as a preliminary step in identifying genes that contribute to natural variation in hippocampal Fe, Cu, and Zn content. We used ICP-MS to measure the concentrations of these metals in 120-day-old mice from 30 strains of the BXD/TY panel. The BXD/Ty recombinant inbred strain panel is well-suited for complex trait analysis, as all strains are genotyped with a dense marker set and have been phenotyped extensively for neurobehavioral traits and hippocampal gene expression. We observed a wide-range of hippocampal Fe, Cu, and Zn concentrations across the BXD strains. These concentrations were related to systemic Fe status, but not to Fe, Cu, and Zn elsewhere in the brain. The three metals also showed strong covariance, suggestive of overlap in their regulatory pathways. We identified two QTL, on chromosomes 14 and 9, most strongly associated with Cu but also suggestively associated with Fe (chr. 14) and Zn (chr. 9). We also performed genetic correlational analyses with existing data on these strains and revealed associations with cognitive, anxiety-related, and alcohol-related phenotypes. Covariance of these metals with gene expression is also discussed. This work shows that hippocampal Fe, Cu, and Zn are under polygenic influence and that trace metal regulation is associated with hippocampus-related behaviors. Future work will elucidate the genes underlying the two QTL identified, to aid in identifying homologous genetic variants in human populations, which may underlie altered trace metal homeostasis and related neurological disease.

Genetical Genomics of Behavior: A Novel Chicken Genomic Model for Anxiety Behavior

“…Such an enrichment gives us a great deal of confidence about the genes that have been identified, as well as providing far greater evidence for their effects on behavior, in many cases, than was available previously. The 6 genes with previous implications [SLC31A (Jones et al 2008;Lagus et al 2010;Goerlich et al 2012), ADAM10 (Postina et al 2004;Schmitt et al 2006;Bell et al 2008;Jorissen et al 2010), GABRB2 (Moriarty 1995;Marín et al 1997;Salvatierra and Arce 2001), APBP2 (Kirov et al 2008), and STK17A and RABBGTB (Kõks et al 2004)] have a variety of effects in neural tissue or on behavior. ADAM10 is required for embryonic brain development, (Jorissen et al 2010), protects against amyloid plaque formation (Postina et al 2004), increases synaptogenesis (Bell et al 2008), and also causes behavioral differences in learning and memory (Schmitt et al 2006).…”

“…SLC31A and RABGGTB have both been shown to have some links with anxiety behavior and memory. SLC31A (a copper transporter) has been linked with depression in rats (Lagus et al 2010) and chickens exposed to social isolation and restraint stress (Goerlich et al 2012), and genetic correlations suggest a link between copper and anxiety behaviors in BXD mice (Jones et al 2008). RABGGTB has been linked with fear responsiveness in rats (Kõks et al 2004).…”

Characterization of Periodic Acid-Schiff-Positive Granular Deposits in the Hippocampus of SJL/J Mice

“…TOXICOLOGIC PATHOLOGY formation of granules. The hippocampus has unique regulatory demands for metals, such as copper, iron and zinc, as each contributes to synaptic plasticity, and copper and zinc are pivotal neuromodulators in synapses (Jones, Beard, and Jones 2008). The exact mechanisms of general cuprizone toxicity are not fully understood so far.…”

Zinc enhances ethanol modulation of the α1 glycine receptor

“…For example, Jones et al (2008) suggest a significant correlation between hippocampal zinc levels and voluntary alcohol drinking. Female recombinant inbred BXD mice with relatively lower concentrations of zinc in hippocampus showed higher alcohol acceptance in a two-bottle choice drinking test.…”