Neural grafting reverses prenatal drug-induced alterations in hippocampal PKC and related behavioral deficits

Steingart, Ruth A.; Silverman, William F.; Barron, Susan; Slotkin, Theodore A.; Awad, Yaser; Yanai, Joseph

doi:10.1016/s0165-3806(00)00123-1

Cited by 44 publications

(102 citation statements)

References 42 publications

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“…It should be noted that similar significance levels were shown with a two-tailed t-test for all major findings. Sex differences were considered in the analysis and in agreement with earlier work with prenatal heroin treatment, 16,17 the initial analysis of variance did not identify any significant interaction between treatment and sex; accordingly results from males and females are presented together. Significance for all tests was assumed at the level P < 0.05.…”

Section: Specific Methodsmentioning

confidence: 83%

“…[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. 16,21,41,46 This appears to be a major mechanism of these behavioral defects.…”

Section: Discussionmentioning

confidence: 99%

“…Heroin administration paradigm was based on our previous studies showing neurobehavioral deficits after its prenatal administration. 17,23 Pregnant female mice received a daily subcutaneous injection of 10 mg kg À1 of heroin or saline on GD9-GD18, the period when most brain structures develop. 24 The drug was not given after that period in order to prevent neonatal withdrawal, which would adversely affect offspring-maternal interaction.…”

Section: Specific Methodsmentioning

confidence: 99%

“…Animals were anesthetized with an intraperitoneal injection of 80 mg kg À1 pentobarbital and grafted on a stereotaxic apparatus with 2500 neurospheres (100-200 cells per neurosphere) at a volume of 2-5 ml using a 10 ml Hamilton syringe into each hippocampus at the following coordinates: 1.8 mm posterior to bregma, 71.5 mm lateral from the midline and 1.7 mm below calvarium. 17,30 DMEM media was chosen as the control solution. The issue of an appropriate control has been coped with since the days of grafting of embryonic differentiated cells, as opposed to neural progenitors.…”

Section: Specific Methodsmentioning

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: Specific Methodsmentioning

confidence: 83%