Developmental manganese neurotoxicity in rats: Cognitive deficits in allocentric and egocentric learning and memory

Amos‐Kroohs, Robyn M.; Davenport, Laurie L.; Atanasova, Nina A.; Abdulla, Zuhair I.; Skelton, Matthew R.; Vorhees, Charles V.

doi:10.1016/j.ntt.2016.10.005

Cited by 29 publications

(14 citation statements)

References 56 publications

(84 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dopaminergic dysfunction in the striatum is known to impair CWM (Braun et al, 2012; Braun et al, 2015). We reported that developmental MnOE (using the same dosing paradigm as here) alters neostriatal DA and causes CWM deficits (Amos-Kroohs et al, 2016a; Amos-Kroohs et al, 2017) and DA effects were found by others (Kern et al, 2010; McDougall et al, 2008; Moreno et al, 2009). One study showed that MnOE (750 μg, p.o., P1-21) in rats decreased striatal DA transporter (DAT), DA transmission, and reduced performance on a fixed ratio-1 operant task but not on higher ratio schedules of reinforcement (McDougall et al, 2008), further implicating striatal DA, albeit indirectly (McDougall et al, 2008; Vorhees and Williams, 2016).…”

Section: Discussionsupporting

confidence: 70%

“…Although an essential nutrient in low doses, excess Mn (Mn over-exposure (MnOE)) has adverse effects (Aschner and Aschner, 2005; Racette et al, 2012; Roth, 2009). In rodents developmental MnOE results in cognitive deficits, altered locomotor activity, and blunted acoustic startle responses (Amos-Kroohs et al, 2015; Amos-Kroohs et al, 2016a; Amos-Kroohs et al, 2017; Tran et al, 2002b). MnOE in children is associated with decreased IQ, reduced school performance, and behavioral disinhibition (Bouchard et al, 2011; Khan et al, 2011; Khan et al, 2012; Lucchini et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Developmental manganese, lead, and barren cage exposure have adverse long-term neurocognitive, behavioral and monoamine effects in Sprague-Dawley rats

Sprowles

Amos‐Kroohs

Braun

et al. 2018

Neurotoxicology and Teratology

Self Cite

View full text Add to dashboard Cite

Developmental stress, including low socioeconomic status (SES), can induce dysregulation of the hypothalamic-pituitary-adrenal axis and result in long-term changes in stress reactivity. Children in lower SES households experience more stress and are more likely to be exposed to environmental neurotoxins such as lead (Pb) and manganese (Mn) than children in higher SES households. Co-exposure to stress, Pb, and Mn during early development may increase the risk of central nervous system dysfunction compared with unexposed children. To investigate the potential interaction of these factors, Sprague-Dawley rats were bred, and litters born in-house were culled on postnatal day (P)1 to 6 males and 6 females. One male and female within each litter were assigned to one of the following groups: 0 (vehicle), 10 mg/kg Pb, 100 mg/kg Mn, or 10 mg/kg Pb + 100 mg/kg Mn (PbMn), water gavage, and handled only from P4-28 with half the litters reared in cages with standard bedding (29 litters) and half with no bedding (Barren; 27 litters). Mn and PbMn groups had decreased anxiety, reduced acoustic startle, initial open-field hypoactivity, increased activity following (+)-methamphetamine, deficits in egocentric learning in the Cincinnati water maze (CWM), and deficits in latent inhibition conditioning. Pb increased anxiety and reduced open-field activity. Barren-reared rats had decreased anxiety, CWM deficits, increased startle, and initial open-field hyperactivity. Mn, PbMn, Pb Barren-reared groups had impaired Morris water maze performance. Pb altered neostriatal serotonin and norepinephrine, Mn increased hippocampal serotonin in males, Mn + Barren-rearing increased neostriatal serotonin, and Barren-rearing decreased neostriatal dopamine in males. At the doses used here, most effects were in the Mn and PbMn groups. Few interactions between Mn, Pb, and rearing stress were found, indicating that the interaction of these three variables is not as impactful as hypothesized.

show abstract

Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Developmental manganese, lead, and barren cage exposure have adverse long-term neurocognitive, behavioral and monoamine effects in Sprague-Dawley rats

Sprowles

Amos‐Kroohs

Braun

et al. 2018

Neurotoxicology and Teratology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The formation of LTP is considered as a potential cellular mechanism in learning and memory processes. According to the findings of previous studies 21 , our study revealed that α-Syn KO did not influence the LTP under normal conditions. This might be because LTP is mainly caused by postsynaptic mechanisms in the CA3-CA1 pathway, but the α-Syn effects on synaptic transmission are predominantly presynaptic 22 .…”

Section: Discussionsupporting

confidence: 81%

“…An elevation of Mn concentration in the hippocampus was detected in Mn-treated mice. Consistent with this notion, the elevation of Mn concentration in the hippocampus resulted in deficits in spatial memory, loss of neurons, and impairment in hippocampal LTP 21,24 . However, between Mn-treated WT and α-Syn KO mice, no significant difference was shown in neuronal injury or Mn concentration in the hippocampus.…”

Section: Discussionsupporting

confidence: 52%

Alpha-synuclein is involved in manganese-induced spatial memory and synaptic plasticity impairments via TrkB/Akt/Fyn-mediated phosphorylation of NMDA receptors

Liu

et al. 2020

Cell Death Dis

View full text Add to dashboard Cite

Manganese (Mn) overexposure produces long-term cognitive deficits and reduces brain-derived neurotrophic factor (BDNF) in the hippocampus. However, it remains elusive whether Mn-dependent enhanced alpha-synuclein (α-Syn) expression, suggesting a multifaceted mode of neuronal toxicities, accounts for interference with BDNF/TrkB signaling. In this study, we used C57BL/6J WT and α-Syn knockout (KO) mice to establish a model of manganism and found that Mn-induced impairments in spatial memory and synaptic plasticity were related to the α-Syn protein. In addition, consistent with the long-term potentiation (LTP) impairments that were observed, α-Syn KO relieved Mn-induced degradation of PSD95, phosphorylated CaMKIIα, and downregulated SynGAP protein levels. We transfected HT22 cells with lentivirus (LV)-α-Syn shRNA, followed by BDNF and Mn stimulation. In vitro experiments indicated that α-Syn selectively interacted with TrkB receptors and inhibited BDNF/TrkB signaling, leading to phosphorylation and downregulation of GluN2B. The binding of α-Syn to TrkB and Fyn-mediated phosphorylation of GluN2B were negatively regulated by BDNF. Together, these findings indicate that Mn-dependent enhanced α-Syn expression contributes to further exacerbate BDNF protein-level reduction and to inhibit TrkB/Akt/Fyn signaling, thereby disturbing Fyn-mediated phosphorylation of the NMDA receptor GluN2B subunit at tyrosine. In KO α-Syn mice treated with Mn, spatial memory and LTP impairments were less pronounced than in WT mice. However, the same robust neuronal death was observed as a result of Mn-induced neurotoxicity.

show abstract

“…Amos-Kroohs et al (2015) observed increased offspring mortality rate as a consequence of MnOE. For these reasons, the pre-weaning MnOE paradigm was selected, as this results in elevated Mn concentrations in blood and brain (Amos-Kroohs et al, 2015;Vorhees et al, 2014) which is considered to result in learning and memory deficits (Amos-Kroohs et al, 2017). Given that alterations in Fe transport mechanisms may elevate Mn uptake, our experimental model employed a combination of FeD-induced effects and consequent exacerbation of MnOE toxicity (Park et al, 2013;Kim et al, 2014;Meltzer et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Metal bashing: iron deficiency and manganese overexposure impact on peripheral nerves

Amos‐Kroohs

Usach

Piñero

et al. 2019

Journal of Toxicology and Environmental Health, Part A

Self Cite

View full text Add to dashboard Cite

Iron (Fe) deficiency (FeD) and manganese (Mn) overexposure (MnOE) may result in several neurological alterations in the nervous system. Iron deficiency produces unique neurological deficits due to this elemental role in central nervous system (CNS) development and myelination, which might persist after normalization of Fe in the diet. Conversely, MnOE, is associated with diverse neurocognitive deficits. Despite these well-known neurotoxic effects on the CNS, the influence of FeD and MnOE on the peripheral nervous system (PNS) remains poorly understood. The aim of the present investigation was to examine the effects of developmental FeD and MnOE or their combination on the sciatic nerve of young and adult rats. The parameters measured included divalent metal transporter 1 (DMT1), transferrin receptor (TfR), myelin basic protein (MBP) and peripheral myelin protein 22 (PMP22) expression, as well as Fe levels in the nerve. Our results showed that FeD produced a significant reduction in MBP and PMP22 content at P29, which persisted at P60 after Fe-sufficient diet replenishment regardless of Mn exposure levels. At P60 MnOE significantly increased sciatic nerve Fe content and DMT1 expression. However, the combination of FeD and MnOE produced no marked motor skill impairment. Evidence indicates that FeD appears to hinder developmental peripheral myelination, while MnOE may directly alter Fe homeostasis. Further studies are required to elucidate the interplay between these pathological conditions.

show abstract

Developmental manganese neurotoxicity in rats: Cognitive deficits in allocentric and egocentric learning and memory

Cited by 29 publications

References 56 publications

Developmental manganese, lead, and barren cage exposure have adverse long-term neurocognitive, behavioral and monoamine effects in Sprague-Dawley rats

Developmental manganese, lead, and barren cage exposure have adverse long-term neurocognitive, behavioral and monoamine effects in Sprague-Dawley rats

Alpha-synuclein is involved in manganese-induced spatial memory and synaptic plasticity impairments via TrkB/Akt/Fyn-mediated phosphorylation of NMDA receptors

Metal bashing: iron deficiency and manganese overexposure impact on peripheral nerves

Contact Info

Product

Resources

About