Systems genetic analysis of the effects of iron deficiency in mouse brain

Jellen, Leslie C.; Unger, Erica L.; Lu, Lu; Williams, Robert W.; Rousseau, Sarah; Wang, Xusheng; Earley, Christopher J.; Allen, Richard P.; Miles, Michael F.; Jones, Byron C.

doi:10.1007/s10048-012-0321-1

Cited by 36 publications

(29 citation statements)

References 35 publications

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“…Glt-1 expression showed a strong negative correlation with VMB iron. 40 While this study did not measure protein, it could, nonetheless, indicate that iron deficiency occurs with increased glial uptake of Glu, consistent with the primary hypothesis of this project of increased glutamatergic activity in RLS.…”

Section: H Mrs)mentioning

confidence: 48%

Thalamic glutamate/glutamine in restless legs syndrome

et al. 2013

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Objective: To evaluate possible abnormal increase in thalamic glutamate/glutamine levels for restless legs syndrome (RLS) indicating increased glutamatergic activity producing arousal that at night disrupts and shortens sleep. Methods:1 H MRS of the right thalamus was performed using a 1.5 T GE MRI scanner and the PROBE-P (PRESS) on 28 patients with RLS and 20 matched controls. The Glx signal (combination of mostly glutamate [Glu] and glutamine [Gln]) was assessed as a ratio to the total creatine (Cr). This study tested 2 primary hypotheses: 1) higher thalamic Glx/Cr for patients with RLS than controls; 2) thalamic Glx/Cr correlates with increased wake during the sleep period.Results: The Glx/Cr was higher for patients with RLS than controls (mean 6 SD 1.20 6 0.73 vs 0.80 6 0.39, t 5 2.2, p 5 0.016) and correlated significantly with the wake time during the sleep period (r 5 0.61, p 5 0.007) and all other RLS-related polysomnographic sleep variables (p , 0.05) except for periodic leg movements during sleep (PLMS)/hour. Conclusions:The primary findings introduce 2 new related dimensions to RLS: abnormalities in a major nondopaminergic neurologic system and the arousal disturbance of sleep. The strong relation of the arousal sleep disturbance to glutamate and the lack of relation to the PLMS motor features of RLS contrasts with the reverse for dopamine of a limited relation to arousal sleep disturbance but strong relation to PLMS. Understanding this dichotomy and the interaction of these 2 differing systems may be important for understanding RLS neurobiology and developing better treatments for RLS. Neurology 1 H MRS 5 proton magnetic resonance spectroscopy; mI 5 myo-inositol; NAA 5 N-acetylaspartate; PLMS 5 periodic leg movements during sleep; PSG 5 polysomnography; RLS 5 restless legs syndrome; SWS 5 slow-wave sleep; VMB 5 ventral midbrain; WDSP 5 wake during the sleep period.Restless legs syndrome (RLS) is a rest-induced, movement-responsive, mostly nocturnal, urge to move the legs commonly associated with periodic leg movements during sleep (PLMS).1 Sleep disruption is the primary factor producing most of the morbidity of moderate to severe RLS. 2Patients with RLS, however, rarely report problems with excessive daytime sleep despite total sleep times averaging less than 5.5 hours.3 Untreated subjects with RLS who have no other sleep disorders (e.g., sleep apnea) have not been found in any clinical study to have a problem falling asleep while driving nor do they show the degree of frontal lobe cognitive deficits expected from their sleep loss. 4 Dopaminergic treatments provide effective treatment for RLS symptoms and dramatically reduce PLMS but in most studies fail to significantly reduce the sleep loss, arousals during sleep, 5-7 and abnormal cycling alternating pattern of sleep occurring with RLS. 8 Dopaminergic systems do not appear to be primary for producing the RLS sleep/wake arousal.If not dopamine, then what produces this RLS arousal pattern? A review of potential nondopaminergic systems led t...

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Section: H Mrs)mentioning

confidence: 48%

Thalamic glutamate/glutamine in restless legs syndrome

et al. 2013

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“…Iron is considered to be a risk factor in sPD per se , (Berg et al, 2001) and recently we showed that it co-operates with paraquat in neurotoxicity (Yin et al, 2011). This strain is also quite sensitive to disruption in iron regulation as a result of being fed an iron-poor diet (Jellen et al, 2012). That this strain is also among the most susceptible to MPTP toxicity and exactly how iron and MPTP toxicity in this strain are related remains to be seen.…”

Section: Discussionmentioning

confidence: 99%

Systems analysis of genetic variation in MPTP neurotoxicity in mice

et al. 2013

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We analyzed genetic variation in severity of neuronal damage using the known dopaminergic neurotoxicant, MPTP, as a prototypical chemical denervation agent. Male mice from ten members of the BXD family of recombinant inbred strains received 12.5 mg/kg MPTP s.c. (vs. saline) and 48 h later brains were taken for multiple related biochemical analyses. Striatal dopamine (DA) and its metabolites, DOPAC and HVA, and serotonin and its metabolite, 5-HIAAA, were analyzed by HPLC. DA turnover was assessed using DOPAC/DA and HVA/DA ratios. Striatal tyrosine hydroxylase (TH), glial fibrilary acidic protein (GFAP), and iron content in ventral midbrain were quantified. All dopamine measures, as well as TH and GFAP, demonstrated wide, genotype-dependent differences in response to MPTP. Serotonin was largely unaffected. Principal components analysis (PC) on difference values, saline minus MPTP, for DA, DOPAC, HVA, and TH, yielded a dominant principal component. The PC trait residuals for each genotype were compared against complementary expression data for striatum of the same strains. Three transcripts representing Mtap2, Lancl 1, and Kansl1l were highly correlated with the PC, as was the difference score, MPTP minus saline for GFAP. This systems approach to the study of environmental neurotoxicants holds promise to define individual genetic differences that contribute to variability in susceptibility to risk factors for diseases such as Parkinson’s disease.

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“…ID diet also produces peripheral organ (e.g., liver and spleen) iron deficiency and may also produce an anemia in some animals (Yin, et al, 2012), thus raising concerns as to the relevance of peripheral ID effects on the ID effects found in brain. Studies utilizing a broad range of BXD RI mice strains under normal and ID condition have not identified any significant relation between peripheral iron status and VMB iron status (Jellen, et al, 2012; Yin, et al, 2012). In cell culture models, where the issue of anemia or altered peripheral metabolism are not operational, changes in DAergic system with diminished iron concentrations were similar to DAergic system changes seen in ID animal (Connor, et al, 2009; Unger, et al, 2008; Wiesinger, et al, 2007).…”

Section: Discussionmentioning

confidence: 98%

Low brain iron effects and reversibility on striatal dopamine dynamics

Unger

Bianco

Jones

et al. 2014

Experimental Neurology

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Iron deficiency (ID) in rodents leads to decreased ventral midbrain (VMB) iron concentrations and to changes in the dopamine (DA) system that mimic many of the dopaminergic changes seen in RLS patient where low substantia nigra iron is a known pathology of the disease. The ID-rodent model, therefore, has been used to explore the effects that low VMB iron can have on striatal DA dynamics with the hopes of better understanding the nature of iron-dopamine interaction in Restless Legs Syndrome (RLS). Using a post-weaning, diet-induced, ID condition in rats, the No-Net-Flux microdialysis technique was used to examine the effect of ID on striatal DA dynamics and it reversibility with acute infusion of physiological concentrations of iron into the VMB. This study replicated prior findings by showing that the ID condition is associated with increased extracellular striatal DA, reduced striatal DA uptake, and blunted DA-2-receptor-agonist feedback enhancement of striatal DA uptake. Despite the increase in extracellular striatal DA, intracellular striatal DA, as determined in tissue homogenates, was decrease in the ID rat. The study’s key finding was that an infusion of physiological concentrations of iron into the VMB reversed the ID-induced increase in extracellular striatal DA and the ID-induced decrease in intracellular striatal DA but had no effect on the ID-induced changes in DA uptake or on the blunted DA-uptake response to quinpirole. In summary, the ID-rodent model provides highly reproducible changes in striatal DA dynamics that remarkably parallel dopaminergic changes seen in RLS patients. Some but not all of these ID-induced changes in striatal DA dynamics were reversible with physiological increases in VMB iron. The small changes in VMB iron induced by iron infusion likely represent biologically relevant changes in the non-transferrin-bound labile iron pool and may mimic circadian-dependent changes that have been found in VBM extracellular iron.

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Systems genetic analysis of the effects of iron deficiency in mouse brain

Cited by 36 publications

References 35 publications

Thalamic glutamate/glutamine in restless legs syndrome

Thalamic glutamate/glutamine in restless legs syndrome

Systems analysis of genetic variation in MPTP neurotoxicity in mice

Low brain iron effects and reversibility on striatal dopamine dynamics

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