Reversal of heroin neurobehavioral teratogenicity by grafting of neural progenitors

Sophia Katz, Tamir Ben-Hur, Tamar L. Ben-Shaanan, Joseph Yanai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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) γ 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 PKCγ and PKCβII 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 PKCγ and PKCβII (p = 0.0337 and p = 0.0265 respectively) to cholinergic receptor stimulation. The effects were specific as the PKCα 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.

Original languageEnglish
Pages (from-to)38-49
Number of pages12
JournalJournal of Neurochemistry
Volume104
Issue number1
DOIs
StatePublished - Jan 2008

Keywords

  • Heroin
  • Morris water maze
  • Neural progenitors grafting
  • Pre-natal exposure
  • Protein kinase C isoforms
  • Septohippocampal cholinergic innervation

Fingerprint

Dive into the research topics of 'Reversal of heroin neurobehavioral teratogenicity by grafting of neural progenitors'. Together they form a unique fingerprint.

Cite this