EXTENSIVE REINNERVATION OF THE HIPPOCAMPUS BY EMBRYONIC BASAL FOREBRAIN CHOLINERGIC NEURONS GRAFTED INTO THE SEPTUM OF NEONATAL RATS WITH SELECTIVE CHOLINERGIC LESIONS

Reconstruction of the septohippocampal pathways by axons extending fro m embryonic cholinergic neuroblasts grafted into the neuron-depleted s eptum has been explored in the neonatal rat by using a novel lesioning and grafting protocol. Neonatal ablation of the basal forebrain choli nergic projection neurons, accompanied by extensive bilateral choliner gic denervation of the hippocampus and neocortex, was produced at post natal day (PD) 4 by 192 immunoglobulin (IgG)-saporin intraventricularl y. Four days later, cholinergic neuroblasts (from embryonic day 14 rat s) were implanted bilaterally into the neuron-depleted septum by using a microtransplantation approach. The results show that homotopically implanted septal neurons survive and integrate well into the developin g septal area, extending axons caudally along the myelinated fimbria-f ornix and supracallosal pathways that-are able to reach the appropriat e targets in the denervated hippocampus and cingulate cortex as early as 4 weeks postgrafting. Moreover, the laminar innervation patterns es tablished by the graft:derived axons closely resembled the normal ones and remained essentially unchanged up to at least 6 months, which was the longest postoperative time studied. The reinnervating fibers rest ored tissue choline acetyltransferase activity (up to 50% of normal) i n the dorsal hippocampus and the parietooccipital cortex. Retrograde l abeling with Fluoro-Gold from the host hippocampus combined with immun ocytochemistry confirmed that most of the projecting neurons, indeed, were cholinergic. The results suggest that the graft-host interactions that are necessary for target-directed axon growth are present in the septohippocampal system during early postnatal maturation. Thus, the present approach may contribute to overcome the functional limitations inherent in the use of ectopically placed intrahippocampal transplant s. (C) 1996 Wiley-Liss, Inc.