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A recently introduced quantitative radioautographic technique was used to characterize the striatal dopaminergic deficit in weaver mutant mice and to evaluate the extent of DA reinnervation resulting from cell suspension grafts of fetal ventral mesencephalic tissue. Brain slices from normal mice and unilaterally grafted weaver mice were incubated in [3H]DA, in the presence of desipramine and pargyline, 3–5 months after graft surgery. Semi-thin sections from the fixed and resin-embedded slices were subsequently exposed on tritium sensitive film and afterwards dipped in nuclear emulsion for light microscope radioautography. Alternate slices were embedded in Epon for post-embedding tyrosine hydroxylase (TH) immunocytochemistry. The grain density of the film radioautographs matched well the distribution of TH positive fibers. Both methods revealed an almost complete absence of DA axons in the dorsomedial quadrant of the weaver neostriatum and an increasing density of DA innervation towards the ventrolateral areas. In the light microscope radioautographs, only the ventral striatum (i.e. nucleus accumbens and olfactory tubercle) and a narrow ventral and periventricular zone of the caudate-putamen were covered by silver grain clusters typical of DA varicosity labeling. Such labeled varicosities were nevertheless found in reduced numbers in the lateral portion of both nucleus accumbens and the olfactory tubercle. The remaining neostriatum was overlaid by diffuse silver grains, suggesting a deficient DA uptake and storage mechanism in the residual DA fibers in this region. Immunocytochemistry using antibodies specific for DA or TH provided further evidence that the residual DA innervation in the weaver neostriatum was biochemically defective. Weaver mice with grafts of ventral mesencephalic tissue in the right neostriatum showed an amphetamine-induced rotational bias to the contralateral side, which was not seen in the sham-operated animals. In contrast to the intrinsic weaver neostriatal DA innervation, DA fibers of graft origin exhibited the normal, clustered type of varicosity labeling. The computerized image analysis of silver grain density in film radioautographs was calibrated by counting these labeled varicosities in selected areas of light microscope radioautographs from the same sections. Results showed a mean DA reinnervation of neostriatal tissue surrounding the graft of about 20%, in some cases up to 80%, of the density seen in wild type mice, with a gradual decrease with distance up to 1–1.4 mm from the graft. The ventral parts of the neostriatum, which contained higher numbers of residual intrinsic DA fibers, were much more sparsely reinnervated than the dorsal and dorsomedial areas. These data show that a quantitatively significant DA reinnervation of the weaver neostriatum can be provided by fetal mesencephalic cell suspension grafts and that these DA fibers become functional, at least with respect to their DA uptake and storage mechanisms, in a neostriatal environment where intrinsic weaver DA axons are strongly deficient. However, observations in long-term weaver mice (9 months after transplantation) suggested that the graft-derived DA fiber outgrowth was reduced with time in the affected striatum, in spite of good survival of the grafted neurones.

Summary Weaver (wv/wv) mutant mice lose most granule cells of the cerebellum during the first 2 weeks of postnatal life; ‘Purkinje cell degeneration’ (pcd/pcd) mutants lose virtually all Purkinje cells between postnatal days 17 and 45. Both these neurological mutations are autosomal recessive. We designed a breeding protocol that, in theory, should result in the production of mice with a doubly mutant,wv/wv*pcd/pcd, genotype. Some of the offspring of such crosses had a novel cerebellar phenotype in which both granule and Purkinje cells underwent degeneration, leading to a highly atrophic cortex. This phenotype is what would be expected inwv/wv*pcd/pcd double mutants, and the proportion of such progeny obtained fits with genetic expectations. We propose that (1)wv/wv*pcd/pcd double mutant mice are viable, and (2) the anatomical phenotype of such mice is a combined expression of the component phenotypes.

Attempts to reconstruct the damaged nigrostriatal pathway in experimental models of Parkinson disease have thus far been carried out in animals with neurotoxically induced dopamine deficiency. The present study establishes the weaver (wv/wv) mutant mouse as a genetic model of chronic striatal dopamine denervation by demonstrating a marked decrease of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta. Moreover, grafts of embryonic ventral mesencephalon taken from genetically normal mice and transplanted into the lateral ventricle of adult weaver mutants can survive and grow in the mutant host environment, express tyrosine hydroxylase immunoreactivity, and reinnervate the target regions of the recipient. These results provide evidence of integration of graft and host tissue and suggest that transplantation of dopamine neurons may be effectively applied to overcome nigrostriatal degeneration of genetic etiology.

Sigmund Freud, the acclaimed founder of psychoanalysis, invested nine years of his early scientific effort investigating animal histology, cell biology and basic neuroscience prior to concentrating on human nervous and mental disorders. Through his histological studies Freud provided coherent evidence suggesting that the protoplasm consists of a contractile fibrillary network, the present‐day cytoskeleton; he was one of the original founders of the fibrillary theory on the structure of the protoplasm. Concerning the biology of the cell nucleus, Freud appears to have been the first author who documented movements of nucleoli in nerve cells, a phenomenon presently referred to as nuclear rotation. In certain instances, Freud's observations antedate later views by more than half a century and are important to our current understanding of cell structure and basic processes of intracellular motility.