Reversal of heroin neurobehavioral teratogenicity by grafting of neural progenitors.
A major objective in identifying the mechanisms underlying neurobehavioral teratogenicity in an animal model is the possibility of designing therapies that reverse or offset teratogen-induced neural damage. In our previous studies, we identified deficits in hippocampal muscarinic cholinergic receptor-induced translocation of protein kinase C (PKC) gamma as the likely central factor responsible for the adverse behavioral effects of pre-natal heroin exposure. Neural progenitors (NP) have the ability to recover behavioral deficits after focal hippocampal damage. Therefore, we explored whether behavioral and synaptic defects could be reversed in adulthood by neural progenitor grafting. Pregnant mice were injected daily with 10 mg/kg of heroin on gestational days 9-18. In adulthood, offspring showed deficits in the Morris maze, a behavior dependent on the integrity of septohippocampal cholinergic synaptic function, along with the loss of the PKCgamma and PKCbetaII responses to cholinergic stimulation. Mice that were exposed pre-natally to heroin and vehicle control mice were then grafted in adulthood with NP. Importantly, most grafted cells differentiated to astrocytes. NP reversed the behavioral deficits (p = 0.0043) and restored the normal response of hippocampal PKCgamma and PKCbetaII (p = 0.0337 and p = 0.0265 respectively) to cholinergic receptor stimulation. The effects were specific as the PKCalpha isoform, which is unrelated to the behavioral deficits, showed almost no changes. Neural progenitor grafting thus offers an animal model for reversing neurobehavioral deficits originating in septohippocampal cholinergic defects elicited by pre-natal exposure to insults.
Katz
Sophia
S
The Ross Laboratory for Studies in Neural Birth Defects, Department of Anatomy and Cell Biology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Ben-Hur
Tamir
T
Ben-Shaanan
Tamar L
TL
Yanai
Joseph
J
D000014:Abnormalities, Drug-Induced / Q000473:pathology* / Q000503:physiopathology / Q000601:surgery*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D005260:Female; D003932:Heroin / Q000633:toxicity*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D009294:Narcotics / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D020033:Protein Isoforms / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000502:physiology*
D009294:Narcotics; D020033:Protein Isoforms; D003932:Heroin; D011493:Protein Kinase C