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

Administration of heroin or phenobarbital to pregnant mice evokes neurochem ical and behavioral deficits consequent to disruption of septohippocampal c holinergic innervation. The present study evaluates the relationship betwee n the drug-induced biochemical changes and the behavioral deficits, applyin g two different approaches: neural grafting and within-individual correlati ons of biochemistry and behavior. Mice were exposed transplacentally to phe nobarbital or heroin on gestational days 9-18 and tested in adulthood. Drug -exposed mice displayed impaired radial arm maze performance, increases in presynaptic choline transporter sites (monitored with [H-3]hemicholinium-3 binding), upregulation of membrane-associated protein kinase C (PKC) activi ty, and desensitization of the PKC response to a cholinergic agonist, carba chol. Grafting of cholinergic cells to the impaired hippocampus reversed th e behavioral deficits nearly completely and restored basal PKC activity and the PKC response to carbachol to normal: the drug effects on hemicholinium -3 binding were also slightly obtunded by neural grafting, but nevertheless remained significantly elevated. There were significant correlations betwe en the performance in the eight-arm maze and both basal PKC activity and PK C desensitization, and to a lesser extent, between behavioral performance a nd hemicholinium-3 binding. Taken together, these findings indicate an inex tricable link between the biochemical effects of prenatal drug exposure on the PKC signaling cascade and adverse behavioral outcomes. The ability of n eural grafting to reverse both the drug-induced changes in PKC and behavior s linked to septohippocampal cholinergic function suggest a mechanistic lin k between this signaling pathway and neurobehavioral teratology caused by h eroin or phenobarbital. (C) 2000 Elsevier Science B.V. All rights reserved.