Purkinje Cell Replacement by Intracerebellar Neuronal Implants in an Animal Model of Heredodegenerative Ataxia: An Overview

Summary

Functional recovery through neuronal transplantation requires a precise synaptic integration of replaced neurons. Working on the cerebellum of adult Purkinje cell degeneration (pcd) mice, we have shown that the missing Purkinje cells can be replaced by grafting cerebellar primordia taken from normal mouse embryos. This replacement results from a selective invasion of Purkinje cells which leave the graft and penetrate into the mutant molecular layer, and from the terminal sprouting of host cerebellar axons providing the grafted Purkinje cells with a specific synaptic investment. The in vitro electrophysiological study of these grafted neurons discloses:

• 1. typical all-or-none climbing fiber responses;

• 2. graded parallel fiber EPSPs; and

• 3. inhibitory postsynaptic potentials, all with characteristics similar to those recorded in control mice.

Furthermore, immunocytochemical studies with Purkinje cell markers have shown that, when grafted, Purkinje cells are located in molecular layer regions no further than 0.6 mm from the host deep nuclei, they are able to send appropriate projections, and to establish synaptic contacts on nuclear neurons, partially reconstructing the nucleocortical projection. These results point to the possibility of neuronal replacement by specific synaptic integration of the grafted neurons into the deficient cerebellar circuitry, conditions needed for functional restoration in systems connected in a point-to-point manner.