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A mechanism-based complementary screening approach for the amelioration and reversal of neurobehavioral
Joseph Yanai1, Yael Brick-Turin, Sharon Dotan
1The Ross Laboratory for Studies in Neural Birth Defects, Department of Anatomy and Cell Biology The Hebrew University-Hadassah Medical School, Box 12272, 91120 Jerusalem, Israel. yanai@md.huji.ac.il
Abstract:
The identification of mechanisms and outcomes for neurobehavioral teratogenesis is critical to our ability to develop therapies to ameliorate or reverse the deleterious effects of exposure to developmental neurotoxicants. We established mechanistically-based complementary models for the study of cholinergic systems in the mouse and the chick, using both environmental neurotoxicants (chlorpyrifos, perfluoroalkyls) and drugs of abuse (heroin, nicotine, PCP). Behavioral evaluations were made using the Morris maze in the mouse, evaluating visuospatial memory related to hippocampal cholinergic systems, and imprinting in the chick, examining behavior dependent on cholinergic innervation of the IMHV. In both models we demonstrated the dependence of neurobehavioral deficits on impairment of cholinergic receptor-induced expression, and translocation of specific PKC isoforms. Understanding this mechanism, we were able to reverse both the synaptic and behavioral deficits with administration of neural progenitors. We discuss the prospects for clinical application of neural progenitor therapy, emphasizing protocols for reducing or eliminating immunologic rejection, as well as minimizing invasiveness of procedures through development of intravenous administration protocols.
Insights
This study identifies how developmental neurotoxicants harm brain development and shows neural progenitor therapy can reverse these effects, offering hope for new treatments.
Area of Science:
- Neuroscience
- Developmental Toxicology
- Regenerative Medicine
Background:
- Neurobehavioral teratogenesis from developmental neurotoxicant exposure requires understanding of underlying mechanisms for therapeutic development.
- Cholinergic systems are crucial for cognitive functions and are vulnerable to environmental toxins and drugs of abuse.
Purpose of the Study:
- To elucidate the mechanisms of neurobehavioral deficits induced by developmental neurotoxicants.
- To investigate the potential of neural progenitor therapy for reversing neurobehavioral impairments.
Main Methods:
- Established complementary mouse and chick models to study cholinergic systems.
- Utilized environmental neurotoxicants (chlorpyrifos, perfluoroalkyls) and drugs of abuse (heroin, nicotine, PCP).
- Assessed behavioral deficits using the Morris maze (mouse) and imprinting (chick), and analyzed molecular mechanisms involving cholinergic receptor expression and PKC isoform translocation.
Main Results:
- Demonstrated that neurobehavioral deficits are linked to impaired cholinergic receptor-induced expression and PKC isoform translocation.
- Successfully reversed both synaptic and behavioral deficits using neural progenitor administration.
- Identified a key molecular mechanism underlying neurodevelopmental toxicity.
Conclusions:
- Neural progenitor therapy shows promise for reversing neurobehavioral deficits caused by developmental neurotoxicants.
- Further research is needed to optimize clinical application, focusing on reducing immunologic rejection and invasiveness via intravenous administration.
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