Niveles de la autoestima

The Lurcher mutant mouse appeared as a spontaneous mutation in the Medical Research Council's Radiological Research Unit breeding colony in 1954. First described by Philips (1960), the Lurcher gene (Lc) is an autosomal dominant murine mutation. It is located on linkage group XI o f chromosome 6 and is lethal when homo

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second to third postnatal week. Lurcher heterozygotes develop a characteristic "swaying o f their hind quarters when moving, during which they fall from one side to the other as if their legs have given way" (Phillips, 1960). This ataxia has been confirmed by others (Fortier et al., 1987).

The postnatal development o f the Lurcher mutant mouse has been studied for a number o f years and the development o f the lesion in the animal characterized both qualitatively and quantitatively. Caddy and Biscoe (1975) revealed that the neurological basis o f the phenotypic ataxia seen in the adult Lurcher heterozygote is primarily a cerebellar defect: there was a marked reduction in the size o f the Lurcher cerebellum when compared to wild-type littermates. Histological analysis o f the Lurcher cerebellum by these authors indicated a complete absence o f Purkinje cells at the boundary o f the granule cell and molecular layers, both o f which were also considerably reduced in thickness. Quantitative analysis o f the Lurcher mutation has revealed a rapid and complete loss o f the Purkinje cells during postnatal development. Caddy and Biscoe (1979) report that by postnatal day 26 (P26) only 10% o f Purkinje cells present in the wild-type remain in the Lurcher, and this figure probably falls to zero by P90. Granule cell and inferior olivary neuron numbers are also reduced in the adult Lurcher and are 10% and 25% of the wild-type values respectively (Caddy and Biscoe, 1979). The degeneration o f inferior olivary neurons in the Lurcher has been confirmed by Heckroth and Eisenman (1991), who report a similar reduction in numbers. Granule cell loss in the Lurcher has been reported in premigratory, migrating and cells o f the granule cell layer (Swisher and Wilson, 1977).

Purkinje cell abnormalities are evident as early as P8 in the Lurcher mutant mouse: the stems o f the dendrites are thicker but the spread o f the dendritic trees is reduced and less branched when compared to the wild-type; the dendrites are studded with ectopic spines; the axons contain numerous varicosities; the nuclear chromatin is clumped and the nuclear membrane irregular; the organelles o f the dendritic cytoplasm are disorganised; the rough endoplasmic reticulum fails to form Nissl bodies; and the mitochondria appear distended with spherical profiles (Dumesnil-Bousez and Sotelo, 1992). Despite the early onset o f atypical structures, the synaptic investment o f Purkinje cells by parallel fibres is comparable to that in the wild-type in early postnatal Lurchers (Dumesnil-Bousez and Sotelo, 1992). However, by PIO the rate o f parallel fibre-Purkinje cell synaptogenesis is decreased as dendritic development is retarded. The dendrites are thick and stunted and fail to reach the pial surface. Retraction o f the dendrites follows with a dramatic decline

F ig u re 3. Golgi-Cox stained Purkinje cells in 100 pm thick sections. Micrographs taken from material donated by K .W .T . Caddy using Nomarski optics. (A) Postnatal day 15 wild-type mouse. Note the numerous spines on the more distal dendrites. (B and 0 ) Postnatal day 15 heterozygous Lurcher mutant mice in which the cells are clearly abnormal. The pial surface is indicated in each of the micrographs (arrows) to illustrate the reduced thickness of the molecular layer in the Lurcher. Scale bar = 50 pm.

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Golgi-Cox stained Purkinje cells from PI 5 wild-type and Lurcher mutant mice can be compared in Figure 3.

The poly innervation o f Purkinje cells by climbing fibres is retained by most Lurcher Purkinje cells until cell death (Rabacchi et al., 1992a). Using anterograde transport o f WGA-HRP from the inferior olive, Heckroth and Eisenman (1988) have shown that the climbing fibres fail to enter the molecular layer in the adult Lurcher. Instead, the dense climbing fibre "nests" around the Purkinje cell somata are maintained during late postnatal development (P13-P15) and continue to form synapses with somatic spines (Heckroth et al., 1990). Lurcher Purkinje cell axons also fail to acquire the characteristic basket cell pinceau terminals (Heckroth, 1992).

The later stages o f Lurcher Purkinje cell degeneration are marked by an increase in the number o f lysosomes and free ribosomes, vacuolation o f the cytoplasm, cell lysis and removal o f the debris by macrophages (Caddy and Biscoe, 1979).

The Lurcher mutation is unique in producing such a complete and specific loss o f Purkinje cells during postnatal development. Other cerebellar mutants, for example: nervous, nr (Landis, 1973); reeler, rl (Mariani et al., 1977); weaver, wv (Rakic and Sidman, 1973a); staggerer, sg (Sotelo and Changeux, 1974) and stumbler, stu (Caddy et al., 1981) suffer some loss o f Purkinje cells, but not at such a comprehensive and rapid rate. The one mutation with a comparable rate and extent o f Purkinje cell loss is Purkinje cell degeneration, pcd (Mullen et al., 1976). However, pcd abnormalities, unlike those o f the Lurcher, are not confined to the cerebellum and its afferents.

In contrast to the concomitant reductions in the presynaptic granule cells and inferior olivary neurons, the postsynaptic targets o f the Purkinje cell remain relatively unaffected in the Lurcher. Caddy and Biscoe (1979) have recorded almost identical numbers o f the deep cerebellar nuclei (DCN) neurons in adult Lurcher and wild-type mice. In a more detailed study o f the adult Lurcher DCN, Heckroth (1994a and b) has revealed a slight reduction in the numbers o f interposed and dentate nuclei neurons, whilst the fastigial nucleus is unaltered. The smaller neurons o f the DCN were preferentially affected and only 63% o f those present in the wild-type remained in the Lurcher, whilst the larger neurons suffered a mild, 20% or less, reduction. The small neurons o f the DCN have been shown to have a considerable projection to the inferior olive (Tolbert et al., 1976) that is less prevalent in the cells o f the fastigial nucleus. Small interposed and dentate nuclei neurons therefore suffer the greatest deficit o f target following cell loss in the Lurcher inferior olive, a phenomenon that may explain the pattern o f degeneration in the DCN o f the mutant (Heckroth, 1994a).

It is interesting to note that the pattern o f degeneration in the Lurcher seems to follow responses to the loss o f postsynaptic targets rather than deafferentation. On the basis o f their morphological observations, Caddy and Biscoe (1979) proposed that the Lurcher gene acts directly on the cerebellar Purkinje cell itself. The cascade o f cell death o f other neuronal cell types was considered to be a response to the loss o f postsynaptic target, rather than any intrinsic defect.