Neural grafting as a tool for the study and reversal of neurobehavioral birth defects

The transplantation of fetal neurons has gained notoriety in recent years for its perceived potential to reverse neurological deficits caused by loss of one or another neuronal population. The present paper describes a neural grafting approach employed by our laboratory to gain more insight into the drug-induced neurobehavioral teratogenicity. Mice were exposed prenatally to phenobarbital by feeding the barbiturate to the pregnant dam on gestation days 9-18. Heroin exposure was accomplished by injecting dams during the same gestational period. At maturity, the drug-exposed offspring displayed profound deficits in specific behavioral tasks, suggesting alterations in the septohippocampal cholinergic pathway. Biochemically, we observed increased presynaptic activity in the pathway, which was not accompanied by a corresponding reduction in postsynaptic activity. Rather, there was a general hyperactivation along the different postsynaptic phases. In contrast, we noted a desensitization of protein kinase C activity in response to the exposure of a cholinergic agonist to the drug-exposed offspring. Subsequent transplantation of embryonic cholinergic cells from normal mice to the impaired hippocampus reversed the behavioral deficits, whereas sham-operated controls exhibited no improvement. Concomitantly, all the biochemical alterations studied, both presynaptic and postsynaptic, were either partially or completely reversed following grafting.