The herbicide glyphosate inhibits hippocampal long-term potentiation and learning through activation of pro-inflammatory signaling

Izumi, Yukitoshi; O’Dell, Kazuko A.; Zorumski, Charles F.

doi:10.1038/s41598-023-44121-7

Cited by 2 publications

(1 citation statement)

References 58 publications

(83 reference statements)

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“…Lee et al wrote in their abstract: "Altogether, our study suggests p53 as an activity-dependent transcription factor that mediates the surface expression of AMPAR, permits hippocampal synaptic plasticity, represses autism-like behavior, and promotes hippocampus-dependent learning and memory" [177]. A study published in 2023 demonstrated that glyphosate activates microglia via toll-like 4 receptor (TLR4) and triggers cellular stress, resulting in impaired hippocampal plasticity and learning [200].…”

Section: Pin1's Crucial Role For P53 Expression and Activationmentioning

confidence: 84%

Is Autism a PIN1 Deficiency Syndrome? A Proposed Etiological Role for Glyphosate

Seneff,

Kyriakopoulos,

Nigh

2024

Preprint

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Autism is a neurodevelopmental disorder whose prevalence has increased dramatically in the United States over the past two decades. It is characterized by stereotyped behaviors and impairments in social interaction and communication. In this paper, we present evidence that autism can be viewed as a PIN1 deficiency syndrome. PIN1 (Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1) is a peptidylprolyl cis/trans isomerase, and it has widespread influences in biological organisms. Broadly speaking, PIN1 deficiency is linked to many neurodegenerative diseases, whereas PIN1 overexpression is linked to cancer. Death associated protein kinase 1 (DAPK1) strongly inhibits PIN1, and the hormone melatonin inhibits DAPK1. Melatonin deficiency is strongly linked to autism. It has recently been shown that glyphosate exposure to rats inhibits melatonin synthesis due to increased glutamate release from glial cells and increased expression of metabotropic glutamate receptors. Glyphosate's inhibition of melatonin leads to a reduction in PIN1 availability in neurons. In this paper, we show that PIN1 deficiency can explain many of the unique morphological features of autism, including increased dendritic spine density, missing or thin corpus callosum and reduced bone density. We show how PIN1 deficiency disrupts the functioning of powerful high level signaling molecules, such as nuclear factor erythroid 2-related factor 2 (NRF2) and p53. Dysregulation of both of these proteins has been linked to autism. Severe depletion of glutathione in the brain resulting from chronic exposure to oxidative stressors and extracellular glutamate leads to oxidation of the cysteine residue in PIN1, inactivating the protein and further contributing to PIN1 deficiency. Impaired autophagy leads to increased sensitivity of neurons to ferroptosis. Finally, we consider evidence of the potential toxic effects of the mRNA SARS-CoV-2 vaccines in the light of metabolic defects in autism, and we propose that children with autism would be especially sensitive to damage from the vaccines.

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Section: Pin1's Crucial Role For P53 Expression and Activationmentioning

confidence: 84%

Is Autism a PIN1 Deficiency Syndrome? A Proposed Etiological Role for Glyphosate

Seneff,

Kyriakopoulos,

Nigh

2024

Preprint

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Glyphosate as a direct or indirect activator of pro-inflammatory signaling and cognitive impairment

Izumi,

O’Dell,

Zorumski

2023

Neural Regeneration Research

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Glyphosate-based herbicides are widely used around the world, making it likely that most humans have significant exposure. Because of habitual exposure, there are concerns about toxicity including neurotoxicity that could result in neurological, psychiatric, or cognitive impairment. We recently found that a single injection of glyphosate inhibits long-term potentiation, a cellular model of learning and memory, in rat hippocampal slices dissected 1 day after injection, indicating that glyphosate-based herbicides can alter cognitive function. Glyphosate-based herbicides could adversely affect cognitive function either indirectly and/or directly. Indirectly, glyphosate could affect gut microbiota, and if dysbiosis results in endotoxemia (leaky gut), infiltrated bacterial by-products such as lipopolysaccharides could activate pro-inflammatory cascades. Glyphosate can also directly trigger pro-inflammatory cascades. Indeed, we observed that acute glyphosate exposure inhibits long-term potentiation in rat hippocampal slices. Interestingly, direct inhibition of long-term potentiation by glyphosate appears to be similar to that of lipopolysaccharides. There are several possible measures to control dysbiosis and neuroinflammation caused by glyphosate. Dietary intake of polyphenols, such as quercetin, which overcome the inhibitory effect of glyphosate on long-term potentiation, could be one effective strategy. The aim of this narrative review is to discuss possible mechanisms underlying neurotoxicity following glyphosate exposure as a means to identify potential treatments.

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The herbicide glyphosate inhibits hippocampal long-term potentiation and learning through activation of pro-inflammatory signaling

Cited by 2 publications

References 58 publications

Is Autism a PIN1 Deficiency Syndrome? A Proposed Etiological Role for Glyphosate

Is Autism a PIN1 Deficiency Syndrome? A Proposed Etiological Role for Glyphosate

Glyphosate as a direct or indirect activator of pro-inflammatory signaling and cognitive impairment

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