Embryonic and adult neurons interact to allow Purkinje cell replacement in mutant cerebellum

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Abstract
It has often been proposed that one way of replacing degenerating neurons in the brain is to implant embryonic neurons of the same type1. However, in the case of so-called 'point-to-point' systems, as opposed to the 'paracrine' systems which mainly involve local release of neurotransmitter, functional recovery requires a precise re-establishment of the missing circuitry. We recently showed that in one point-to-point system, the cerebellum of adult mice homozygous for the mutation Purkinje cell degeneration (pcd) 2, missing Purkinje cells can be replaced by grafting cerebellar primordia from normal mouse embryos3,4. Here, we present studies of the cellular mechanisms underlying this successful replacement. Grafted Purkinje cells leave the graft to migrate along stereotyped pathways to their final position in the deficient molecular layer, where they receive synaptic contacts from adult host neurons. Both the detailed timetable and the precise cellular interactions observed are remarkably similar to those occurring during normal development. Our results suggest that the deficient molecular layer exerts a selective neurotropic effect on neurons of the missing category, and that the embryonic neurons are able to respond to this signal during a period defined by their own internal clock. We also raise the possibility that embryonic Purkinje cells can induce in adult neural cells a new type of plasticity, that of recreating a permissive microenvironment for the integration of embryonic neurons.