Mutant mice as a model for cerebellar ataxia

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Abstract

Not later than two synapses after their arrival in the cerebellar cortex all excitatory afferent signals are subsequently transformed into inhibitory ones. Guaranteed by the exceedingly ordered and stereotyped synaptic arrangement of its cellular elements, the cerebellar cortex transmits this inhibitory result of cerebellar integration exclusively via Purkinje cells (PCs) in a precise temporal succession directly onto the target neurons of the deep cerebellar and vestibular nuclei. Thus the cerebellar cortex seems to produce a temporal pattern of inhibitory influence on these target neurons that modifies their excitatory action in such a way that an activation of muscle fibers occurs which progressively integrates the intended motion into the actual condition of the motoric inventory. In consequence, disturbances that affect this cerebellar inhibition will cause uncoordinated, decomposed and ataxic movements, commonly referred to as cerebellar ataxia. Electrophysiological investigations using different cerebellar mouse mutants have shown that alterations in the cerebellar inhibitory input in the target nuclei lead to diverse neuronal responses and to different consequences for the behavioural phenotype. A dependence between the reconstitution of inhibition and the behavioural outcome seems to exist. Obviously two different basic mechanisms are responsible for these observations: (1) ineffective inhibition on target neurons by surviving PCs; and (2) enhancement of intranuclear inhibition in the deep cerebellar and vestibular nuclei. Which of the two strategies evolves is dependent upon the composition of the residual cell types in the cerebellum and on the degree of PC input loss in a given area of the target nuclei. Motor behaviour seems to deteriorate under the first of these mechanisms whereas it may benefit from the second. This is substantiated by stereotaxic removal of the remaining PC input, which eliminates the influence of the first mechanism and is able to induce the second strategy. As a consequence, motor performance improves considerably. In this review, results leading to the above conclusions are presented and links forged to human cerebellar diseases.

Introduction

Cerebellar ataxia may originate from a large variety of very heterogeneous hereditary and non-hereditary diseases (for rev. see Rosenberg, 1995, Klockgether and Dichgans, 1997). The group of autosomal dominant cerebellar ataxias (ADCA) was formerly classified on the basis of the behavioural and pathological phenotype (Königsmark and Weiner, 1970, Weiner and Lang, 1989, Harding, 1982, Harding, 1993) but recent progress in the identification of the genes responsible has reformed and clarified the classification of these diseases substantially. Currently, the different types of spinocerebellar ataxia (SCA1-7), the dentatorubral–pallidolysian atrophy (DRPLA) and the group of episodic ataxias (EA) constitute the ADCAs, for all of which the genes have been mapped (for rev. see Rosenberg, 1995, Klockgether and Dichgans, 1997).

The recessively inherited ataxias include Friedreich's ataxia — the most frequent of all ataxias — the group of early onset ataxias (EOCA), ataxia teleangiectasia, ataxia with isolated vitamin E deficiency, cerebrotendinious xanthomatose, abetalipoproteinemia, Refsum's disease and granule cell layer hypoplasia (Norman, 1940, Jervis, 1954, Harding, 1984, Rosenberg, 1995, Klockgether and Dichgans, 1997).

Non-hereditary ataxia may evolve in developmental malformations, cerebellar infarction, neoplasms, paraneoplastic degeneration, viral infections or nutritional deficiencies. The cerebellum and Purkinje cells (PCs), moreover, are particularly vulnerable to ethanol abuse (Jones et al., 1973, Hanson et al., 1978), organic solvent exposure (Yamada, 1964, Allen et al., 1975) and diverse intoxications (Igata, 1971, Appel et al., 1975, Bahiga et al., 1978, Adams and Mayhew, 1985) during both development and adulthood.

Common to all these disorders and besides the clinical signs produced by the various disturbances in extracerebellar areas, is a combination of cerebellar motor symptoms like instability of posture and gait, incoordination, atactic reaching and grasping, tremor, dysmetria, muscular hypotonia, and various impairments in the fine control of movements (Holmes, 1917, Holmes, 1939, Dow and Moruzzi, 1958, Gilman et al., 1981, Harding, 1982). In most cases only a few of these symptoms become relatively severe after cerebellar injury or in the course of cerebellar disease (Dow and Moruzzi, 1958, Gilman et al., 1981, Harding, 1982, Ito, 1984). The particular individual combination of clinical signs is thought to depend primarily on the developmental stage at onset, the location, the specificity and the extent of the defect (Dow and Moruzzi, 1958, Gilman et al., 1981, Harding, 1982). However, on the basis of these symptoms the location of a cerebellar lesion can be attributed only roughly to medial or lateral cerebellar regions; a more precise prediction is almost impossible (Maurice-Williams, 1975, Mancall and McEntee, 1965, Desclin, 1974, Dow and Moruzzi, 1958, De Jong, 1979, Gilman et al., 1981). Moreover, the severity of a lesion often does not correlate with the severity of the symptoms (Haubek and Lee, 1979, Koller et al., 1981, Diener et al., 1986). Apart from secondary degenerative or compensatory mechanisms in the cerebellar cortex itself, a major reason for this inexact localization of a cerebellar defect and the disconformity of symptoms with the severity, may be neuronal reactions in the deep cerebellar (DCN) and vestibular nuclei (VN). As the complete product of cerebellar cortical processing is focussed on the PCs (Purkinje, 1838, Palay and Chan-Palay, 1974, Sotelo and Alvarado-Mallart, 1991) and these in turn are directly connected with the DCN and VN (Palay and Chan-Palay, 1974, Palkovits et al., 1977, Ito, 1984, Voogd et al., 1985), the outcome of a cortical deterioration of whatever origin is transmitted directly to these nuclei or, in the case of PC degeneration, the cerebellar input is partially or completely removed from the target neurons in these areas. Thus, all disturbances in the cerebellar cortex finally concern the function or the number of PCs, or both. Since the normal synaptic action of PCs on their target neurons is inhibitory in nature (Ito and Yoshida, 1964, Ito and Yoshida, 1966), cerebellar pathology will lead to alterations in the inhibitory action of the cerebellar cortex on the DCN and VN.

It is important to emphasize that at least a portion of these target neurons in the DCN and VN are extrinsic and give rise to cerebello-thalamic, cerebello-rubral, cerebello-vestibular, cerebello-reticular and vestibulo-spinal connections (for rev. see: Gilman et al., 1981, Ito, 1984, Voogd et al., 1985) and thus exert an influence on motor performance at almost every level of planning and execution. It is also of significance to recall that the cerebellar cortex acts upon this main route of sensori-motor processing as a sidepath (Ito, 1984, Ito, 1989, Ito, 1990) via PCs. In consequence, the motor symptoms in cerebellar ataxia are essentially determined by the plastic behaviour of the neurons in the direct cerebellar target nuclei. However, although cerebellar cortical plasticity and cerebellar learning as well as vestibular compensation have been intensively studied in the last decades and immense effort invested in the classification of the different types of cerebellar ataxia, much less attention has been directed to the plastic and compensatory potency of DCN and VN target neurons and their influence on the resulting motor behaviour in the course of cerebellar disease.

In this review, particular attention is focussed on the question of the existence of general responses from the cerebello-vestibular system to PC malfunction and loss, and on promoting an understanding of how a particular cerebellar disorder finally determines the behavioural phenotype of the individuum affected. A synopsis of almost two decades of investigations in our laboratory on this issue using neurophysiological, stereotaxic, immunocytochemical, stereological, morphological and behavioural techniques is given and set in the light of related findings from other investigators.

An outstanding advantage in studying cerebellar ataxia, compared to most other neurological disorders, is the availability of a large number of mouse mutations that affect the cerebellum and serve as naturally designed models with a large variety of disturbances during different developmental stages and with highly diverse histological and behavioural phenotypes (Green, 1981). We used six of these cerebellar mutants for our comparative studies: Purkinje cell degeneration (pcd/pcd) (Mullen et al., 1976), leaner (tgla/tgla) (Sidman et al., 1965), weaver (wv/wv) (Lane, 1965), staggerer (sg/sg) (Sidman et al., 1962), nervous (nr/nr) (Sidman and Green, 1970) and Lurcher (Lc/+) (Phillips, 1960). In two of these, pcd and Lc, virtually all PCs degenerate postnatally (Mullen et al., 1976, Swisher and Wilson, 1977, Landis and Mullen, 1978, Caddy and Biscoe, 1979). In wv the vast majority of granule cells are lost (Lane, 1965, Rakic and Sidman, 1973a, Sotelo and Changeux, 1974b). In nr and tgla reciprocal alternate parasagittal zones of PCs degenerate (Sidman et al., 1965, Yoon, 1969, Sidman and Green, 1970, Landis, 1973, Herrup and Wilczynski, 1982, Zilla et al., 1985). In sg a high but subtotal PC loss is present (Sidman et al., 1962, Sotelo and Changeux, 1974a, Yoon, 1976, Herrup and Mullen, 1979). All of these mutants show characteristic histological defects and clearly distinctive motor behaviour (Green, 1981, Bäurle et al., 1998a). Recently, essential insights into the molecular origin of the defects have been gained by the identification of the genes responsible and their products (for detailed descriptions see the respective sections). However, although the uncovering of the gene and its product is fundamental to the understanding of a hereditary disorder, it does not explain the behaviour of the affected individuum per se. Not until the distribution and function of the altered proteins are known and their influence on the respective neurons and on each specific neuronal context will conclusions with respect to the mechanisms responsible for the behavioural outcome be well-substantiated.

The scope of the present review is still far from filling the gap between genotype and phenotype. What it hopes to do is further the understanding of cerebello-vestibular interaction in cerebellar disorders by providing comparative experimental evidence from different cerebellar mutant mice. The results suggest the existence of generalized and essential plastic mechanisms in the cerebellar target nuclei that respond to functional and numerical alterations in the PC population.

Section snippets

Purkinje cell degeneration mutant

The purkinje cell degeneration (pcd/pcd) mutant is characterized by a rapid and virtually complete loss of PCs (Mullen et al., 1976) between p15 and p45. This late PC degeneration is preceded by an almost completely regular formation of the synaptic pattern of the cerebellar circuitry, as well as the development of the appropriate corticonuclear connectivity (Landis and Mullen, 1978). The mutation acts directly on cerebellar PCs (Mullen, 1977). From studies in pcd-chimeric mice the genetic

Leaner mutant

The leaner (tgla/tgla) mutation (Dickie, 1962) has been mapped on chromosome 8 of the mouse genome (Herrup and Wilczynski, 1982) and is allelic to tottering (tg) and rolling (tgrol) (Meier and MacPike, 1971, Oda, 1973, Adachi et al., 1975, Nakane, 1976). Positional cloning has revealed that the mutation occurs in a gene encoding the voltage-activated calcium channel α1A subunit (Fletcher et al., 1996), which is thought to be the pore-forming subunit of P- and Q-type calcium channels (Tsien et

Weaver mutant

The weaver mutant (wv/wv), first described by Lane (1965), is the result of a single base pair substitution in the gene encoding a G-protein-dependent inwardly rectifying potassium channel protein (GIRK2; Patil et al., 1995). In the cerebellum of wv this channelopathy leads to an almost complete loss of vermal and paravermal granule cells, dying in the external granular cell layer during the first 2 postnatal weeks just prior to their migration and to the formation of parallel fibres (Rakic and

Correlation of the motor behaviour with the physiological and neurochemical mechanisms observed

In normal animals, PC activity in the cerebellar cortex is the result of the complex and highly-ordered cerebellar circuitry and the refined and precise interplay of all neurons and afferents in the microenvironment of the PCs (Marr, 1969, Albus, 1971, Fujita, 1982). The disturbed conditions in the cerebellar cortex of the different mutant mice lead to subsequent functional and/or numerical alterations at the level of the PC population. In the cerebellar targets this generates in turn different

Acknowledgements

We wish to express our appreciation for the technical assistance of Ms H. Wolynski and the secretarial help of Ms I. Knierim. Furthermore, we wish to thank Ms J. Dames for expert help with the English in the manuscript. The first experiments with GABA immunocytochemistry were performed together with Prof. K.P. Hoffmann and Dr A. Horn in Ulm, which we gratefully acknowledge. Parts of the studies were supported by DFG grants Gr276/19,1–5 to U.G.-C., and by the Sonnenfeld Stiftung.

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