Cholinergic synaptic signaling mechanisms underlying behavioral teratogenicity: Effects of nicotine, chlorpyrifos, and heroin converge on protein kinase C translocation in the intermedial part of the hyperstriatum ventrale and on imprinting behavior in an avian model

Izrael, Michal; Zee, Eddy A. van der; Slotkin, Theodore A.; Yanai, Joseph

doi:10.1002/jnr.20287

Cited by 33 publications

(71 citation statements)

References 49 publications

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“…In particular, heroin-induced deficits in eight arm and Morris maze behaviors. [16][17][18][19][20][21][39][40][41] Both of these behavioral tests are affected by the cholinergic septohippocampal projection. [42][43][44] On the biochemical/molecular level, prenatal heroin induced both pre-and postsynaptic hyperactivity in the hippocampal cholinergic innervation, 16,17,23,45 converging on a total abolishment of the specific cholinergic-induced activation of PKCg.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, administration of heroin to pregnant mice induced deficits in hippocampus-related offspring behavior and concomitant cholinergic-related abolishment of protein kinase C (PKC) activation. [16][17][18][19][20][21] Consequently, in the present study we employed our previously established allographic mouse model for the reversal of neurobehavioral defects by transplantation of neural progenitors toward testing the present question. Consistent with our previous studies, genetically heterogeneous HS/Ibg mice 22 were made deficient in the hippocampus-related Morris maze behavior and in its supposed mechanism, PKC function, by exposing them to heroin transplacentally.…”

Section: Introductionmentioning

confidence: 99%

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Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain

2007

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Grafting of neural progenitors has been shown to reverse a wide variety of neurobehavioral defects. While their role of replacing injured cells and restoring damaged circuitries has been shown, it is widely accepted that this cannot be the only mechanism, as therapy can occur even when an insufficient number of transplanted cells are found. We hypothesized that one major mechanism by which transplanted neural progenitors exert their therapeutic effect is by enhancing endogenous cells production. Consequently, in an allographic model of transplantation, prenatally heroin-exposed genetically heterogeneous (HS) mice were made defective in their hippocampal neurobehavioral function by exposing their mothers to heroin (10 mg kg À1 heroin on gestation days 9-18). Hippocampal damage was confirmed by deficient performance in the Morris maze (P < 0.009), and decreased production of endogenous cells in the dentate gyrus by 39% was observed. On postnatal day 35, they received an HS-derived neural progenitors transplant followed by repeated bromodeoxyuridine injections. The transplant returned endogenous cells production to normal levels (P < 0.006) and reversed the behavioral defects (P < 0.03), despite the fact that only 0.0334% of the transplanted neural progenitors survived and that they differentiated mainly to astrocytes. An immunological study demonstrated the presence of macrophages and T cells as a possible explanation for the paucity of the transplanted cells. This study suggests one mechanism for the therapeutic action of neural progenitors, the enhancement of the production of endogenous cells, pointing to future clinical applications in this direction by use of neural progenitors or by analogous cell-inducing techniques.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain

2007

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“…Despite the fact that neuroteratogens affect a variety of regions and innervations, making the ascertaining of the mechanism difficult, a typical finding is cognitive impairment related to specific regions: hippocampus-related behaviors in rodents and the analogous IMHV-related imprinting and their associated cholinergic inputs [16,30,31,43]. Pinpointing the synaptic components that are affected by the neuroteratogen may offset or reverse the defects.…”

Section: Introductionmentioning

confidence: 99%

“…Towards this end, we studied prenatal exposure of mice to teratogens that act directly or indirectly on hippocampal function [25,30,42,43], and identified a defect in the signaling protein, PKCg [25,43]. Initial studies replicated these finding in the chick IMHV-imprinting model [16]. Ascertaining the locus and mechanism underlying the behavioral deficits in mice enabled us to reverse in the mouse both the synaptic and cognitive dysfunction through therapies targeting septohippocampal cholinergic pathways [31,42].…”

Section: Introductionmentioning

confidence: 99%

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A chick model for the mechanisms of mustard gas neurobehavioral teratogenicity

Wormser

Izrael

Zee

et al. 2005

Neurotoxicology and Teratology

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Citation for published version (APA): Wormser, U., Izrael, M., Van der Zee, E. A., Brodsky, B., & Yanai, J. (2005). A chick model for the mechanisms of mustard gas neurobehavioral teratogenicity. Neurotoxicology and Teratology, 27(1), 65-71. DOI: 10.101665-71. DOI: 10. /j.ntt.2004 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. AbstractThe chemical warfare blistering agent, sulfur mustard (SM), is a powerful mutagen and carcinogen. Due to its similarity to the related chemotherapy agents nitrogen mustard (mechlorethamine), it is expected to act as a developmental neurotoxicant. The present study was designed to establish a chick model for the mechanisms of SM on neurobehavioral teratogenicity, free of confounds related to mammalian maternal effects. Chicken eggs were injected with SM at a dose range of 0.0017-17.0 Ag/kg of egg, which is below the threshold for dysmorphology, on incubation days (ID) 2 and 7, and then tests were conducted posthatching. Exposure to SM elicited significant deficits in the intermedial part of the hyperstriatum ventrale (IMHV)-related imprinting behavior. Parallel decreases were found in the level of membrane PKCg in the IMHV, while eliciting no net change in cytosolic PKCg. The chick, thus, provides a suitable model for the rapid evaluation of SM behavioral teratogenicity and elucidation of the mechanisms underlying behavioral anomalies. The results obtained, using a model that controls for confounding maternal effects, may be replicated in the mammalian model and provide the groundwork for studies designed to offset or reverse the SM-induced neurobehavioral defects in both avian and mammals. D

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