Intracerebral neural grafting has over the last decade developed into a powerful tool .for the study of mechanisms underlying functional recovery after brain damage. Our work is focussed on the ability of implants of fetal neurons to re-establish damaged neuronal circuitry and restore transmitter-dependent functional deficits in animal models of .Parkinson's and Huntington's disease, and to modulate development and/or expression of kindling-induced epilepsy. The overriding goal of the project is to explore in further detail the mechanism(s) of action of grafted monoaminergic and GABAergic neurons in these experimental models. The proposed work will focus on 3 major research lines: (1) Studies on the functional properties and regulation of monoaminergic, cholinergic and GABAergic neurons, implanted into the previously denervated striatum or hippocampal formation in adult recipient rats, by means of the intracerebral microdialysis tech- nique. Transmitter overflow (as a measure of transmitter release) will be followed under baseline and stimulated conditions and after various experimental manipulations. (2) Neuroanatomical studies of afferent and efferent connections of grafts of fetal striatal tissue implanted into the ibotenic acid lesioned rat striatum, using combinations of anterograde and retrograde tracers and Golgi-impregnation on both light and EM level. In combination with the microdialysis experiment& we will investigate the role of graft afferents from the host nigrostriatal dopamine system in the activation of GABAergic neurons in the striatal grafts. The experiments are designed to study the .degree to which intrastriatal striatal grafts are incorporated into the host striatal .circuitry, and to what extent such afferent and efferent graft-host connections may be .important in the mediation and regulation of graft function. Our preliminary results .have shown that the intracerebral microdialysis technique can monitor both dopamine, serotonin, noradrenaline, acetylcholine and GABA release from intracerebral grafts. (3) ',Studies on the ability of grafted inhibitory neurons to modulate kindling-induced epilepsy. In particular, we want to pursue further our recent finding that grafts of fetal noradrenergic neurons can suppress the development of kindling-induced seizures in rats made hyperexcitable by a previous lesion of the ascending noradrenergic locus coeruleus system. The results should be important in order to define not only the .possibilities but also the limitations of the neural grafting approach in experimental models of neurodegenerative disease.
