Impairment of Long-term Potentiation and Associative Memory in Mice That Overexpress Extracellular Superoxide Dismutase

Thiels, Edda; Urban, Nathaniel N.; González‐Burgos, Guillermo; Kanterewicz, Beatriz; Barrionuevo, Germán; Chu, Charleen T.; Oury, Tim D.; Klann, Eric

doi:10.1523/jneurosci.20-20-07631.2000

Cited by 200 publications

(192 citation statements)

References 54 publications

(64 reference statements)

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“…Superoxide previously has been established as a signaling molecule required for LTP induction, but its targets have remained elusive (Kishida and Klann 2007;Klann 1998;Thiels et al 2000). Superoxide-induced potentiation and HFS-induced LTP occlude one another, suggesting that they share similar signaling pathways (Knapp and Klann 2002).…”

Section: Discussionmentioning

confidence: 99%

Superoxide-Induced Potentiation in the Hippocampus Requires Activation of Ryanodine Receptor Type 3 and ERK

Huddleston

Tang

Takeshima

et al. 2008

Journal of Neurophysiology

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Huddleston AT, Tang W, Takeshima H, Hamilton SL, Klann E. Superoxide-induced potentiation in the hippocampus requires activation of tyanodine receptor type 3 and ERK. J Neurophysiol 99: 1565-1571, 2008. First published January 16, 2008 doi:10.1152/jn.00659.2007. Reactive oxygen species (ROS) are required for the induction of longterm potentiation (LTP) and behave as signaling molecules via redox modifications of target proteins. In particular, superoxide is necessary for induction of LTP, and application of superoxide to hippocampal slices is sufficient to induce LTP in area CA1. Although a rise in postsynaptic intracellular calcium is necessary for LTP induction, superoxide-induced potentiation does not require calcium flux through N-methyl-D-aspartate (NMDA) receptors. Ryanodine receptors (RyRs) mediate calcium-induced calcium release from intracellular stores and have been shown to modulate LTP. In this study, we investigated the highly redox-sensitive RyRs and L-type calcium channels as calcium sources that might mediate superoxide-induced potentiation. In agreement with previous studies of skeletal and cardiac muscle, we found that superoxide enhances activation of RyRs in the mouse hippocampus. We identified a functional coupling between L-type voltage-gated calcium channels and RyRs and identified RyR3, a subtype enriched in area CA1, as the specific isoform required for superoxide-induced potentiation. Superoxide also enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) in area CA1, and ERK was necessary for superoxide-induced potentiation. Thus superoxide-induced potentiation requires the redox targeting of RyR3 and the subsequent activation of ERK.

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Section: Discussionmentioning

confidence: 99%

Superoxide-Induced Potentiation in the Hippocampus Requires Activation of Ryanodine Receptor Type 3 and ERK

Huddleston

Tang

Takeshima

et al. 2008

Journal of Neurophysiology

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“…Despite the involvement or lack thereof of microglia in MZ neurotoxicity, NADPH oxidase may still be involved in MZ-induced ROS generation. Nonphagocytic NADPH oxidase is important in the central nervous system where it is involved in cell signaling (Infanger et al, 2006), differentiation (Suzukawa et al, 2000), potentiation (Thiels et al, 2000;Knapp and Klann, 2002), and memory (Thiels et al, 2000). Functional subunits of NADPH oxidase have been detected in the neurons of various regions of the mouse brain, including hippocampus, cortex, amygdala, striatum, and thalamus (Serrano et al, 2003;TejadaSimon et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Reactive oxygen species generation by the ethylene-bis-dithiocarbamate (EBDC) fungicide mancozeb and its contribution to neuronal toxicity in mesencephalic cells

Domico

Cooper

Bernard³

et al. 2007

NeuroToxicology

121

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Previous in vitro studies in our laboratory have shown that mancozeb (MZ) and maneb (MB), both widely used EBDC fungicides, are equipotent neurotoxicants that produce cell loss in mesencephalic dopaminergic and GABAergic cells after an acute 24 h exposure. Mitochondrial uncoupling and inhibition were associated with fungicide exposure. Inhibition of mitochondrial respiration is known to increase free radical production. Here the mechanism(s) of neuronal damage associated with MZ exposure was further explored by determining the role that reactive oxygen species (ROS) played in toxicity. Damage to mesencephalic dopamine and GABA cell populations were significantly attenuated when carried out in the presence of ascorbate or SOD indicative of a free radical mediated contribution to toxicity. ROS generation monitored by H 2 O 2 production using Amplex Red increased in a dose-dependent manner in response to MZ. Inhibition of intracellular catalase with aminotriazole had little effect on H 2 O 2 generation, whereas exogenously added catalase significantly reduced H 2 O 2 production demonstrating a large extracellular contribution to ROS generation. Conversely, cells preloaded with the ROS indicator dye DCF showed significant MZ-induced ROS production, demonstrating an increase in intracellular ROS. Both the organic backbone of MZ as well as its associated Mn ion, but not Zn ion were responsible and required for H 2 O 2 generation. The functionally diverse NADPH oxidase inhibitors, diphenylene iodonium chloride, apocynin, and 4-(2-aminoethyl)benzene-sulfonyl fluoride hydrochloride significantly attenuated H 2 O 2 production by MZ. In growth medium lacking cells, MZ produced little H 2 O 2 , but enhanced H 2 O 2 generation when added with xanthine plus xanthine oxidase whereas, in cultured cells, allopurinol partially attenuated H 2 O 2 production by MZ. Minocycline, an inhibitor of microglial activation, modestly reduced H 2 O 2 formation in mesencephalic cells. In contrast, neuronal enriched cultures or cultures treated with MAC-1-SAP to kill microglia, did not show an attenuation of ROS production. These findings demonstrate that Mn-containing EBDC fungicides such as MZ and MB can produce robust ROS generation that likely occurs via redox cycling with extracellular and intracellular oxidases. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeurotoxicology. Author manuscript; available in PMC 2008 November 1. The findings further show that microglia may contribute to but are not required for ROS production by MZ.

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“…Contextual and cued fear conditioning-Associative learning and memory were evaluated by contextual fear conditioning (Paylor et al, 1994;Thiels et al, 2000). Mice were individually transferred to the conditioning chamber, which was housed in a sound-attenuating cubicle.…”

Section: Behavioral Testsmentioning

confidence: 99%

“…Distance, location, and duration of travel bouts, duration of rearing, and occurrence of stereotypical behaviors were recorded. The inner 50% of the chamber surface was considered as the center of the test arena.Contextual and cued fear conditioning-Associative learning and memory were evaluated by contextual fear conditioning (Paylor et al, 1994;Thiels et al, 2000). Mice were individually transferred to the conditioning chamber, which was housed in a sound-attenuating cubicle.…”

mentioning

confidence: 99%

Astrogliosis and behavioral changes in mice lacking the neutral cysteine protease bleomycin hydrolase

et al. 2007

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Bleomycin hydrolase is a multifaceted neutral cysteine protease with a suggested role in antigen presentation, homocysteine-thiolactone metabolism, and Alzheimer's disease pathogenesis. Deletion of the protease in mice results in increased neonatal mortality and dermatopathology. Immunohistochemical and behavioral studies of BLMH knockout mice were undertaken to further evaluate the role of the protease in the brain. No gross abnormalities in the central nervous system were observed upon preliminary histological examination of B6.129Blmh tm1Geh /J null animals. However, glial fibrillary acid protein immunohistochemistry revealed a global reactive astrogliosis in the aged null animals, indicative of undefined brain pathology. The role of BLMH in the brain was further explored by characterizing the behavioral phenotype of hybrid [129S6-Blmh tm1Geh /J X B6.129 Blmh tm1Geh /J]F1 null and littermate controls using multiple behavioral paradigms. In the water maze, deletion of BLMH resulted in poorer performance during water maze probe trials without detectable effect of the mutation on sensorimotor function. In addition, no age-dependent decline in discriminative performance on probe trials was observed in null animals. These data suggest a physiological non-redundant function for BLMH in the central nervous system. Keywords knockout; hippocampus; learning; memory; aging; Alzheimer's disease Bleomycin hydrolase (BLMH) is a highly conserved and unusual aminopeptidase with suggested importance in antigen presentation, homocysteine-thiolactone metabolism, and Alzheimer's disease (AD). A genetic polymorphism within the conserved carboxyterminal region of BLMH is a susceptibility locus for sporadic AD and has been reported by us (Montoya et al., 1998) and others (Papassotiropoulos et al., 2000) to be associated with an approximate two-fold increased risk for development of the disease, although this effect has not been replicated in all studies. Accumulation of β-amyloid peptide derived from proteolytic cleavage of the amyloid precursor protein is believed to be a critical event in the early pathogenesis of Correspondence should be addressed to: John S. Lazo, Department of Pharmacology, University of Pittsburgh, Biomedical Science Tower 3, Suite 10040, 3501 Fifth Avenue, Pittsburgh, PA 15260, E-mail: lazo@pitt.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2008 November 22. Published in final edited form as:Neuroscience. AD (Hardy and Allsop, 1991;Hardy and Higgins, 1992). In vitro st...

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Impairment of Long-term Potentiation and Associative Memory in Mice That Overexpress Extracellular Superoxide Dismutase

Cited by 200 publications

References 54 publications

Superoxide-Induced Potentiation in the Hippocampus Requires Activation of Ryanodine Receptor Type 3 and ERK

Superoxide-Induced Potentiation in the Hippocampus Requires Activation of Ryanodine Receptor Type 3 and ERK

Reactive oxygen species generation by the ethylene-bis-dithiocarbamate (EBDC) fungicide mancozeb and its contribution to neuronal toxicity in mesencephalic cells

Astrogliosis and behavioral changes in mice lacking the neutral cysteine protease bleomycin hydrolase

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