Zinc transporter ZnT3 is involved in memory dependent on the hippocampus and perirhinal cortex

Martel, Guillaume; Hevi, Charles; Kane‐Goldsmith, Noriko; Shumyatsky, Gleb P.

doi:10.1016/j.bbr.2011.04.020

Cited by 61 publications

(55 citation statements)

References 41 publications

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“…ZnT3 KO mice exhibit clear cognitive deficits, but only in animals aged beyond 6 months (Adlard et al, 2010). In other studies, 3- to 4-month-old ZnT3 KO animals show impaired contextual discrimination, spatial working memory, or learned fear extinction (Martel et al, 2010; Martel et al, 2011; Sindreu et al, 2011). …”

Section: Zn2+ and Synaptic Functionmentioning

confidence: 79%

The Neurophysiology and Pathology of Brain Zinc

Sensi¹,

Paoletti²,

Koh³

et al. 2011

J. Neurosci.

299

242

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Our understanding of the roles played by zinc in the physiological and pathological functioning of the brain is rapidly expanding. The increased availability of genetically modified animal models, selective zinc-sensitive fluorescent probes, and novel chelators is producing a remarkable body of exciting new data that clearly establishes this metal ion as a key modulator of intracellular and intercellular neuronal signaling. In this Mini-Symposium, we will review and discuss the most recent findings that link zinc to synaptic function as well as the injurious effects of zinc dyshomeostasis within the context of neuronal death associated with major human neurological disorders, including stroke, epilepsy, and Alzheimer’s disease.

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Section: Zn2+ and Synaptic Functionmentioning

confidence: 79%

The Neurophysiology and Pathology of Brain Zinc

Sensi¹,

Paoletti²,

Koh³

et al. 2011

J. Neurosci.

299

242

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“…Synaptically released Zn 2+ has also been associated with Alzheimer’s disease and pain processing (Deshpande et al, 2009; Duce et al, 2010; Nozaki et al, 2011). Although initial studies did not uncover cognitive deficits in ZnT3KO mice (Cole et al, 2001), recent evidence reveals impaired fear memory (Martel et al, 2010), impaired spatial memory and impaired behavior dependent on hippocampus and perirhinal cortex (Martel et al, 2011), accelerated aging-related decline of spatial memory (Adlard et al, 2010), as well as impairments in spatial working memory and contextual discrimination in mice that lack vesicular Zn 2+ (Sindreu et al, 2011). Our studies, by demonstrating a Zn 2+ -mediated negative feedback loop that reduces Pr at central auditory synapses -- through a specific pathway linking mZnR activation, endocannabinoid synthesis and Pr inhibition -- pave the way for novel in-vivo and behavioral experimental paradigms aimed at further defining the role of Zn 2+ on brain function.…”

Section: Discussionmentioning

confidence: 99%

Synaptic Zn²⁺Inhibits Neurotransmitter Release by Promoting Endocannabinoid Synthesis

Perez‐Rosello¹,

Anderson²,

Schöpfer³

et al. 2013

J. Neurosci.

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Although it is well established that many glutamatergic neurons sequester Zn2+ within their synaptic vesicles, the physiological significance of synaptic Zn2+ remains poorly understood. In experiments performed in a Zn2+-enriched auditory brainstem nucleus -- the dorsal cochlear nucleus -- we discovered that synaptic Zn2+ and GPR39, a putative metabotropic Zn2+-sensing receptor (mZnR), are necessary for triggering the synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). The postsynaptic production of 2-AG, in turn, inhibits presynaptic probability of neurotransmitter release, thus shaping synaptic strength and short-term synaptic plasticity. Zn2+-induced inhibition of transmitter release is absent in mutant mice that lack either vesicular Zn2+ or the mZnR. Moreover, mass spectrometry measurements of 2-AG levels reveal that Zn2+-mediated initiation of 2-AG synthesis is absent in mice lacking the mZnR. We reveal a previously unknown action of synaptic Zn2+: synaptic Zn2+ inhibits glutamate release by promoting 2-AG synthesis.

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“…Tests other than those chosen for inclusion in the current study might reveal differences that were missed here. For example, while performance of zinc transporter-3 knockout mice in the Morris water maze was unaffected when examined in 3-month-old mice, the effects did manifest at 6-months of age (Adlard et al, 2010), and effects could also be uncovered by performing the platform reversal variant of the test instead of the probe-trial variant (Martel et al, 2011). Morris water maze testing in the current study was performed at about 3 months of age (PNDs 70–98); it would be interesting to see if CPO effects manifest at older ages.…”

Section: Discussionmentioning

confidence: 99%

Neurobehavioral assessment of mice following repeated postnatal exposure to chlorpyrifos-oxon

Cole¹,

Fisher²,

Burbacher³

et al. 2012

Neurotoxicology and Teratology

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Chlorpyrifos (CPF), one of the most widely-used organophosphorus (OP) insecticides in agriculture, is degraded in the field to its oxon form, chlorpyrifos-oxon (CPO), which can represent a significant contaminant in exposures to adults and children. CPO is also responsible for the acetylcholinesterase (AChE) inhibition associated with CPF exposures; CPF is converted by liver CYP450 enzymes to CPO, which binds to and inhibits AChE and other serine active-site esterases, lipases and proteases. Young children represent a particularly susceptible population for exposure to CPF and CPO, in part because levels of the plasma enzyme, paraoxonase (PON1), which hydrolyzes CPO, are very low during early development. While a number of studies have demonstrated developmental neurotoxicity associated with CPF exposure, including effects at or below the threshold levels for AChE inhibition, it is unclear whether these effects were due directly to CPF or to its active metabolite, CPO. PON1 knockout (PON1−/−) mice, which lack PON1, represent a highly sensitive mouse model for toxicity associated with exposure to CPF or CPO. To examine the neurobehavioral consequences of CPO exposure during postnatal development, PON1−/− mice were exposed daily from PND 4 to PND 21 to CPO at 0.15, 0.18, or 0.25 mg/kg/d. A neurobehavioral test battery did not reveal significant effects of CPO on early reflex development, motor coordination, pre-pulse inhibition of startle, startle amplitude, open field behavior, or learning and memory in the contextual fear conditioning, Morris water maze, or water radial-arm maze tests. However, body weight gain and startle latency were significantly affected by exposure to 0.25 mg/kg/d CPO. Additionally, from PNDs 15–20 the mice exposed repeatedly to CPO at all three doses exhibited a dose-related transient hyperkinesis in the 20-min period following CPO administration, suggesting possible effects on catecholaminergic neurotransmission. Our previous study demonstrated wide-ranging effects of neonatal CPO exposure on gene expression in the brain and on brain AChE inhibition, and modulation of both of these effects by the PON1Q192R polymorphism. The current study indicates that the neurobehavioral consequences of these effects are more elusive, and suggests that alternative neurobehavioral tests might be warranted, such as tests of social interactions, age-dependent effects on learning and memory, or tests designed specifically to assess dopaminergic or noradrenergic function.

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Zinc transporter ZnT3 is involved in memory dependent on the hippocampus and perirhinal cortex

Cited by 61 publications

References 41 publications

The Neurophysiology and Pathology of Brain Zinc

The Neurophysiology and Pathology of Brain Zinc

Synaptic Zn²⁺Inhibits Neurotransmitter Release by Promoting Endocannabinoid Synthesis

Neurobehavioral assessment of mice following repeated postnatal exposure to chlorpyrifos-oxon

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Zinc transporter ZnT3 is involved in memory dependent on the hippocampus and perirhinal cortex

Cited by 61 publications

References 41 publications

The Neurophysiology and Pathology of Brain Zinc

The Neurophysiology and Pathology of Brain Zinc

Synaptic Zn2+Inhibits Neurotransmitter Release by Promoting Endocannabinoid Synthesis

Neurobehavioral assessment of mice following repeated postnatal exposure to chlorpyrifos-oxon

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Product

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Synaptic Zn²⁺Inhibits Neurotransmitter Release by Promoting Endocannabinoid Synthesis