Brain regions and genes affecting postural control

Progress in Neurobiology 81 (2007) 45–60 www.elsevier.com/locate/pneurobio

Brain regions and genes affecting postural control R. Lalonde a,b,*, C. Strazielle c a

Universite´ de Rouen, Faculte´ de Me´decine et de Pharmacie, INSERM U614, IFRMP, 76183 Rouen Cedex, France b CHUM/St-Luc, Unite´ de Recherche en Sciences Neurologiques, Montre´al, Canada H2X 3J4 c Universite´ Henri Poincare´, Nancy I, Laboratoire de Pathologie Mole´culaire et Cellulaire des Nutriments, INSERM U724 and Service de Microscopie Electronique, Faculte´ de Me´decine, 54500 Vandoeuvre-les-Nancy, France Received 26 February 2006; received in revised form 5 August 2006; accepted 8 November 2006

Abstract Postural control is integrated in all facets of motor commands. The role of cortico-subcortical pathways underlying postural control, including cerebellum and its afferents (climbing, mossy, and noradrenergic fibers), basal ganglia, motor thalamus, and parieto-frontal neocortex has been identified in animal models, notably through the brain lesion technique in rats and in mice with spontaneous and induced mutations. These studies are complemented by analyses of the factors underlying postural deficiencies in patients with cerebellar atrophy. With the gene deletion technique in mice, specific genes expressed in cerebellum encoding glutamate receptors (Grid2 and Grm1) and other molecules (Prkcc, Cntn6, Klf9, Syt4, and En2) have also been shown to affect postural control. In addition, transgenic mouse models of the synucleinopathies and of Huntington’s disease cause deficiencies of motor coordination resembling those of patients with basal ganglia damage. # 2007 Elsevier Ltd. All rights reserved. Keywords: Cerebellum; Basal ganglia; Motor coordination; Motor cortex; Gene knockout

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Cerebral mechanisms underlying equilibrium and balance . . . . . . . . . . . . . . 1.2. Methodological considerations of motor testing in rodents. . . . . . . . . . . . . . Cerebellum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Electrolytic or suction lesions in animals. . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Adult period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Developmental period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. Ascending cerebellar efferent regions . . . . . . . . . . . . . . . . . . . . . . 2.2. Mutant mice with cerebellar atrophy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Motor coordination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Relation between motor coordination and regional brain metabolism 2.3. Null mutations of genes expressed in cerebellum . . . . . . . . . . . . . . . . . . . . 2.3.1. Glutamate receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2. Other genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Plasticity changes in cerebellum of normal rats and monkeys . . . . . . . . . . . 2.5. Patients with cerebellar atrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Patients with lesions of cerebellar efferent regions . . . . . . . . . . . . . . . . . . . Cerebellar afferent regions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: P, postnatal; PKC, protein kinase C; MPTP, methyl-phenyl-tetrahydroyridine; 6-OHDA, 6-hydroxydopamine; CO, cytochrome oxidase; EMG, electromyographic * Corresponding author at: Universite´ de Rouen, Faculte´ de Me´decine et de Pharmacie, INSERM U614, IFRMP, 76183 Rouen Cedex, France. Tel.: +33 2 35 14 82 81; fax: +33 2 35 14 82 37. E-mail addresses: [email protected], [email protected] (R. Lalonde). 0301-0082/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2006.11.005

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R. Lalonde, C. Strazielle / Progress in Neurobiology 81 (2007) 45–60

3.1. 3.2. Basal 4.1. 4.2. 4.3.

Lesions or neurochemical modifications in adult rats . Lesions during rat development . . . . . . . . . . . . . . . . ganglia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical or neurochemical lesions of rat basal ganglia Dopamine depletion in rat or mouse striatum. . . . . . . Genetically modified mice . . . . . . . . . . . . . . . . . . . . 4.3.1. Synucleinopathies. . . . . . . . . . . . . . . . . . . . 4.3.2. Huntington’s disease . . . . . . . . . . . . . . . . . . 4.4. Patients with basal ganglia lesions . . . . . . . . . . . . . . Neocortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Surgical lesions in adult rats . . . . . . . . . . . . . . . . . . 5.2. Surgical lesions during rat development . . . . . . . . . . 5.3. Patients with neocortical lesions. . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction 1.1. Cerebral mechanisms underlying equilibrium and balance Postural control implies correct positioning of body parts relative to the external world. There are two parts of postural control: static and dynamic equilibrium. Static equilibrium maintains a stable stance at rest under the influence of gravity. Dynamic equilibrium concerns body adjustments throughout all phases of movement. Thus, postural control is present at all levels of the motor control hierarchy, in their execution and programming (Fig. 1), with behaviorally meaningful

Fig. 1. Central organization of postural control—the postural execution may be regulated by two mechanisms: (1) feedforward responses result from postural adaptation integrated in motor programming at higher levels (basal ganglia, cerebral cortex, and cerebellum) of motor control; (2) rapid feedback responses from peripheral visual, vestibular, and somatosensory information are generated at lower levels of motor control represented by the brainstem and spinal cord concerned with execution; these responses permit postural adjustments necessary for correcting unexpected disturbances possibly occurring during movement execution.

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integration of many different neural systems, including those associated with cognition (Massion, 1992). Different postural responses can be generated by any voluntary movement. Perturbations initiate strategic and motor programming at higher motor levels involving cerebellum, basal ganglia, and cerebral cortex by means of anticipatory (feedforward) motor responses capable of adaptative learning. In particular, the cerebellum plays a crucial role in sensorimotor learning under some circumstances, but in others, this region affects only the execution of movements (Llinas and Welsh, 1993; Thach et al., 1992b). In addition, a wide range of automatic response patterns driven by visual, vestibular, and somatosensory information occurs at lower levels of functioning for the rapid correction of unexpected disturbances through feedback mechanisms. Postural stability is under the ultimate influence of the final common pathway of the neuromuscular synapse originating from the ventral horn of the spinal cord. Descending ventromedial (vestibulospinal and medial reticulospinal) tracts are of particular importance in the control of posture, because they act on axial and proximal muscles (Lawrence and Kuypers, 1968a,b; Nolte, 1988). The lateral (rubrospinal and corticospinal) tracts are responsible for distal muscles, and thereby play a complementary role in postural stability by affecting the accuracy of movements. In the present review, the effects of brain lesions on motor coordination in tasks requiring balance and equilibrium are summarized. The most studied brain regions include the cerebellum and its afferent/efferent structures, the basal ganglia, and the parieto-frontal neocortex. The main technique employed in rats is electrolytic/suction or neurotoxic lesions of specific brain areas. The behavioral analysis of mice with spontaneous mutations causing cerebellar atrophy and with targeted null mutations has permitted the identification of specific proteins on neuropathology and motor control. These reports are complemented with clinical studies of patients with cerebellar atrophy and ataxia, as well as basal ganglia damage caused by Parkinson’s disease. Transgenic mice have been used as models of Parkinson’s disease and Huntington’s disease.

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1.2. Methodological considerations of motor testing in rodents Postural deficits in mice and rats have principally been screened with stationary beam, suspended wire, inclined grid, and rotorod tests (Lalonde and Strazielle, 1999). For these tests, the main measure used is the latency before falling. In most circumstances, fear of a fall causes animals to exert effort in staying on a bar or grid, thereby assuring the validity of this measure. The mice or rats are placed at an appropriate height (15–50 cm), usually above a matted surface to prevent injury. An involuntary fall is observed whenever the animal drops straight down. More rarely, it jumps up or sideways, thereby appearing to escape from the apparatus in a deliberate fashion. These trials should not be considered as a fall. Instead, the trial should be repeated until the maladaptive response ceases. If not cooperating over several trials, the animal should be removed from analysis. Voluntary jumping mostly occurs when contingencies of the apparatus are inappropriate to the motor capabilities of the animal, or as a result of excessive anxiety and agitation. In the accelerated rotorod task, the speed of rotation gradually increases from approximately 4 to 40 revolutions per minute (rpm), so that the animal has a chance of adjusting to increasing speeds. A voluntary jump is more likely to occur on the constant-speed rotorod if the initial velocity is too high. The same situation occurs if the beam is too slippery, so that a striated beam permitting good traction is preferable to a smooth one. On some rotorods, animals hold on to the beam by passive rotation, as opposed to locomoting forward in synchrony with it. The animals should be removed after one or two complete turns and this behavior considered as equivalent to a fall. Passive rotation is sometimes seen when the rotating beam is small enough so that the animal can easily wrap all four limbs around it, and therefore it is preferable to use a wider beam. As in any behavioral test, excessive agitation may be avoided by taming the animals by hand for a few minutes over several days before the start of testing.

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When the animal is upside down, as in the suspended wire test, dizziness and convulsions may be triggered. In such cases, it is necessary to wait until the animal has completely recovered before initiating the next trial. Optimal performances are achieved when the wire is small enough to fit into the animal’s paw, permitting a tight grasp. Additional measures of motor control have been devised. While some animals move along a stationary beam, others remain immobile. For this reason, distance travelled provides an alternative method of assessing motor coordination in this test. Motor abilities on the stationary beam can also be estimated by counting the number of slips, usually through video analysis rather than direct observation. Foot faults can also be measured in the inclined, vertical, or inverted grid test. The speed of responding can be estimated by latencies before turning upward (negative geotaxic response) or reaching the top of the grid as well as reaching the end of the diagonal bar and climbing in the coat-hanger version of the suspended wire test. 2. Cerebellum 2.1. Electrolytic or suction lesions in animals 2.1.1. Adult period The role of the cerebellum on balance and equilibrium has been investigated in adult rats (Table 1). Schneiderman Fish et al. (1979) assessed the effects of electrolytic lesions of the fastigial or of the dentate nuclei on the stationary beam test. Both lesions caused a deterioration in performances. Joyal et al. (1996) divided rat groups into suction lesions of the midline (vermis and fastigial nucleus) or of the lateral (hemispheres and dentate nucleus) cerebellum or electrolytic lesions of the fastigial nucleus alone. In comparison to sham-operated controls, all three lesions reduced latencies before falling from the stationary beam. Thus, the stationary beam test appears to be sensitive to cerebellar dysfunction. In contrast, only lesions of the midline cerebellum increased latencies before turning upward on an inclined grid (Joyal et al., 1996).

Table 1 Motor coordination after lesions of cerebellar- or basal ganglia-related pathways and neocortex in adult rats or mice Lesion site Cerebellum (except for flocculo-nodular lobe) Fastigial nucleus Dentate nucleus Middle cerebellar peduncle Inferior olive Coeruleo-cerebellar pathway VL-VM thalamus CL thalamus Lateral pallidum Dorsolateral striatum Dorsomedial striatum Substantia nigra pars compacta Posterior parietal cortex Motor cortex

Tests rotorod stationary beam stationary beam; , rotorod rotorod rotorod beam with hurdles rotorod; , stationary beam, suspended wire rotorod; , stationary beam, suspended wire rotorod, stationary beam; , suspended wire stationary beam , stationary beam, suspended wire, rotorod or , rotorod stationary beam , stationary beam

: deficient; ,: unchanged vs. sham-operated controls.

References Caston et al. (1995a,b) Joyal et al. (1996) and Schneiderman Fish et al. (1979) Joyal et al. (2001) and Schneiderman Fish et al. (1979) Gasparri et al. (2003) Gasparri et al. (2003) and Rondi-Reig et al. (1997) Bickford et al. (1992) and Watson and McElligott (1984) Jeljeli et al. (2003) Jeljeli et al. (2000) Jeljeli et al. (1999) Pisa (1988) Thullier et al. (1996a,b) Nash et al. (2005), Rozas et al. (1998) and Tillerson et al. (2002) Kolb and Whishaw (1983) Kolb and Whishaw (1983)

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Moreover, in contrast to the deficient rotorod performance found after cerebellectomy in adult mice (Caston et al., 1995a,b) or in developing rats (see below, Table 1), lesions of the dentate nucleus had no such effect in adult rats (Joyal et al., 2001). Further dissociations between cerebellar subregions have been obtained with the open-field test (Table 1), which estimates ambulatory movements on a wide surface. Although the open-field is not a motor coordination task, some information may be obtained regarding the general motor capacities of the animal. Relative to sham-operated controls, cerebellectomy decreased the motor activity of rats in the openfield (D’Agata et al., 1993). The same decline occurred in rats after lesions of the fastigial but not the dentate nuclei (Berntson and Schumacher, 1980). In summary, lesions of the middle part of the cerebellum could be distinguished from its lateral part on inclined grid (Joyal et al., 1996) and open-field (Berntson and Schumacher, 1980) tests. The deleterious effects of midline lesions are attributable to a loss of postural control caused by interrupted two-way interactions between cerebellar and vestibular systems (Dow et al., 1991; Vidal and Sans, 2004; Voogd, 2004; Walberg, 1972). The deleterious effects of lateral lesions are attributable to a loss in the precision of movements. Electrophysiological recordings in cats have indicated that discharge rates of dentate neurons increased in relation to stepping movements or before visual saccades and some responded to both (Maple-Horvat et al., 1998). The separate contribution of deep cerebellar nuclei to different aspects of motor control has further been delienated in monkeys (Thach et al., 1992a). Fastigial nucleus lesions caused deficits in postural control without action tremor and hypermetria. Interpositus nucleus lesions caused action tremor with minimal gait disturbances and hypermetria. Dentate nucleus lesions caused hypermetria with minimal action tremor and gait disturbances. In addition, dentate nucleus lesions slowed down reaction times and abolished speedier responses seen in sham-lesioned monkeys for predictable as opposed to unpredictable sensory events (Nixon and Passingham, 2001). 2.1.2. Developmental period 2.1.2.1. Ablation lesions. Because motor systems develop in successive stages, the effects of cerebellar lesions on function during the weaning period are liable to differ depending on the postnatal (P) day. Ventromedial tracts responsible for anterior limb movements reach rat cervical spinal cord on embryonic days 13–14 (Gramsbergen, 1998). The rubrospinal tract responsible for posterior limb movements reaches rat lumbar spinal cord on P1, but this pathway appears to be functional only on P14. The corticospinal projection reaches rat lumbar spinal cord on P11. As a consequence of developing motor systems, rats are able to stand on four limbs on P8. From P8 to P14, head movements occur at rest but not while walking. Walking patterns improve on P15–16, but the hindlimbs are still adducted at this stage. From P16 onward, reciprocal activation of flexor and of extensor muscles increases in accuracy and approximates the adult pattern.

The effects of unilateral removal of a cerebellar hemisphere were evaluated at neonatal (P1), end of weaning (P21), and adult (3-month) periods (Molinari et al., 1990; Petrosini et al., 1990). Hemispherectomy on P1 caused maturational delays but with complete recovery for the following responses: body righting, pivoting/crawling, geotaxic reactions, cliff avoidance, midair righting, hindlimb paddling in water, and ladder climbing. In contrast, only partial recovery occurred for suspended wire and stationary beam tests. Thus, in the first set of responses, the opposing cerebellar hemisphere or some other brain region was able to take over the function of the missing hemisphere. But both hemispheres are needed for optimal walking along a narrow surface and holding to a wire in the upside-down position. Body elevation and the tactile placing reaction were not affected at any time. Ablations at P1 promoted better recovery than at P21 and at 3 months with respect to locomotion, stance, and gait. Conversely, P1-ablated rats were worse than the other lesioned groups in regard to hindlimb usage on the suspended wire. It is presumed that correct positioning of the hindlimbs on the suspended wire requires normal development between P1 and P21. In contrast, locomotion, stance, and gait appear to be more susceptible to functional plasticity by early as opposed to late lesions, perhaps at the level of the opposite cerebellar hemisphere or of cerebellar-related pathways. Auvray et al. (1989) bilaterally cerebellectomized (except for the flocculonodular lobe) rat pups on P10, P20, and P24 and examined their performance on the rotorod. The rats were subdivided into groups with daily training before or after ablations and with no training at all. In untrained subgroups, P10 and P20 cerebellectomized rats fell from the rotorod sooner than sham-operated controls on P24 and P30, as did P24 cerebellectomized rats when trained on P30. The P10, P20, and P24 cerebellectomized rats with daily postoperative training had better performances on P30 than non-trained cerebellectomized rats. The performance of the pretrained control group exceeded that of pretrained P10, P20, and, P24 lesioned groups. But there was no significant difference between pretrained and untrained subgroups among P10, P20, and P24 lesioned animals. Thus, postoperative training was more successful than preoperative training as a remedy against the effects of cerebellectomy. Functional plasticity appears to be triggered by postoperative training in extracerebellar structures (or in flocculonodular lobe) starting from P10. But pretraining from P1 to P10, P20, or P24 appears unable to take over from a missing cerebellum. Zion et al. (1990) examined the effects of pre- and postoperative training on P15 cerebellectomized (except for flocculonodular lobe) rat pups. In this study, pretraining began on P10 instead of P1. Naive cerebellectomized rats fell from the rotorod sooner than naive controls on P20, P24, and P30. As in the previous study, cerebellectomized rats with daily postoperative training had better scores than non-trained cerebellectomized rats. These results underline once again the efficacy of postoperative training through neural plasticity in extracerebellar structures (or flocculonodular lobe) to take over at least partially from a missing cerebellum. But unlike the

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previous study, the performance of pretrained cerebellectomized rats did not differ from that of non-lesioned controls. By looking at both experiments together, one may decipher that pretraining from P10 to P15 is more effective than pretraining from P1 to P10, P20, or P24. On one hand, it is presumed that rat pups lesioned on P10 are too immature to take advantage of preoperative training. On the other, rat pups lesioned on P20 or P24 are less susceptible to be aided by preoperative training than rat pups lesioned on P15. Thus, there is something special about the P10 to P15 time window with respect to cerebellar-related neural plasticity. Zion et al. (1990) hypothesize that the increased vulnerability of pups on P20 and P24 relative to P15 is explainable by the change from polyinnervation to monoinnervation of Purkinje cells by climbing fibers originating from the inferior olive, which in rats is completed by P15 (Cre´pel et al., 1976). From these experiments, it appears that once Purkinje cells achieve their mature form of innervation, preoperative training cannot counteract the deleterious effect of cerebellar ablation. But if preoperative training occurs before P15, cerebellar ablation can be counteracted. Between P10 and P15, it is presumed that pretraining triggers some form of neural plasticity outside the cerebellum, whereby the latter becomes less necessary for optimal rotorod performance. These hypotheses may be evaluated by analyzing the behavioral consequences of combined lesions of cerebellum and its target structures, including the inferior olive, during weaning. As mentioned below (Section 3.2), rats with inferior olive lesions given on P15 were impaired on the rotorod (Jones et al., 1995). It remains to be determined whether similar time windows may be generalized to other tests. As pointed out by Harvey and Welsh (1996), these studies demonstrate considerable motor capabilities on the part of rats without a cerebellum. It is therefore of interest to identify those brain regions which contribute to behavioral recovery after cerebellar damage. 2.1.2.2. X-irradiation. Because X-irradiation depletes proliferating cells without affecting postmitotic cells, this method offers the opportunity of investigating the consequences of lesioning specific cell populations (Altman and Bayer, 1978, 1997). Deep cerebellar nuclei, Purkinje and Golgi cells, as well as brainstem precerebellar nuclei (inferior olive, pontine nuclei, and lateral reticular nucleus), are formed prenatally in rats. Basket cell formation peaks on P6–7 and stellate cell formation on P8–11, while granule cells continue to be formed up to P21. The cerebellum of rat pups was exposed to X-rays from P17 to P21 and the motor abilities of the animals were evaluated at juvenile (2 months) and adult (8 months) stages (Brunner and Altman, 1974). The irradiated rats had higher crossing latencies and slips than the unexposed control group on the stationary beam and were also impaired on the rotorod. In a second study (Pellegrino and Altman, 1979), the cerebellum of rats was Xirradiated at one of three periods: P4–15, P4–5, or P8–15. The formation of granule, basket, and stellate stells was severely compromised in the P4–15 group. The degree of granule cell hypoplasia was less extensive in P4–5 rats, but still had considerable morphological impact. In P8–15 rats, basket cells

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were spared, but granule cells and stellate cells were still affected. Deficits on the rotorod were proportional to the severity of neuropathological damage. P4–15 and P4–5 groups were impaired on the rotorod relative to unexposed rats, but the effect was more severe in the former. On the contrary, the more slightly damaged P8–15 group was not impaired. But with increasing task difficulty caused by adding irregularly spaced hurdles or by reducing beam traction, all of the lesioned groups became deficient. In a similar study (Le Marec et al., 1997a), the cerebellum of rat pups was exposed to X-rays on P5–14 or on P10–14 and their behavior evaluated on the rotorod from P23 to P35. The early irradiated animals had more severe granule cell hypoplasia than the late irradiated ones. Although both lesioned groups were impaired on the rotorod relative to unexposed controls, early irradiated rats were more severely affected. On many trials, brain-damaged rats appeared to jump away deliberately from the revolving mast. This maladaptive response might have been prevented by slowing down the initial rotation speed of 20 rpm, as this was probably too close to their maximal capacity. Nevertheless, the results of the studies by Pellegrino and Altman (1979) and by Le Marec et al. (1997a) converge toward the same conclusion with respect to the functional impact of granule cell hypoplasia. In both cases, early irradiated rats with more severe neuropathological damage had poorer performances on the rotorod than rats exposed to radiation at a later stage of development. 2.1.3. Ascending cerebellar efferent regions Ascending cerebellar targets include the red nucleus, situated in the midbrain (Ruigrok, 2004), as well as ventrolateral/ventromedial (VL/VM) and intralaminar nuclei of the thalamus, situated higher up in the diencephalon (Groenewegen and Witter, 2004). The cerebello-rubral tract is considered to be an excitatory synapse, while the cerebellothalamic tract is a mixed excitatory/inhibitory synapse (Allen and Tsukahara, 1974; Massion, 1988). Because the activity of cerebello-rubrospinal neurons is maximal during the flexion phase of the walking cycle in cats (Arshavsky et al., 1988; Orlovsky, 1972), one expects this pathway to be implicated in locomotion on the basis of lesion studies. The motor-related activity of rubral neurons is modifiable by serotonin administration (Schmied et al., 1991), but it is not known whether this neurotransmitter affects whole body movements at this level. Bilateral electrolytic lesions of VL/VM (Jeljeli et al., 2003) or of centrolateral intralaminar (Jeljeli et al., 2000) thalamic nuclei impaired rotorod performance in rats, but without affecting stationary beam and suspended wire tests. These results underline the particular sensitivity of the rotorod in cerebellar-related pathways. To our knowledge, the effects of rubral damage on these types of motor coordination tasks have not been investigated. However, it is known that unilateral ibotenate-induced lesions of the red nucleus, causing gray matter atrophy while sparing axons of passage, disrupted walking rhythms ascertained by video-based kinetic analyses in rats (Muir and Whishaw, 2000).

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More is known regarding the involvement of these nuclei in forelimb reaching tasks. Indeed, unilateral ibotenate-induced lesions of the red nucleus affected rotary movements of the rat forelimb, comprising aiming, pronation, and supination during reaching for stable targets (Whishaw et al., 1998). Moreover, reaching for moving targets was impaired in cats with kainateinduced lesions of the red nucleus (Levesque and FabreThorpe, 1990). Likewise, electrolytic lesions of VL thalamus (Fabre-Thorpe, 1992) or combined lesions of red nucleus and VL thalamus (Lorincz and Fabre-Thorpe, 1997) impaired this task. VL thalamic lesions also reduced the retention of skilled use of the forelimbs in a latch-box task in rats (Thompson et al., 1979). As with lesions of interpositus/dentate nuclei (Glickstein and Yeo, 1990; McCormick and Thompson, 1984), lesions of the red nucleus impaired Pavlovean eyeblink conditioning in rabbits (Rosenfield and Moore, 1983). On the contrary, VL thalamic lesions did not slow down this stimulus-response associative learning task (Sears et al., 1996). Thus, the anatomical circuit of this form of learning appears to include the cerebellum and the red nucleus and to bypass the thalamus. In summary, despite interest in dissociating between the functional impact of cerebello-rubrospinal as opposed to cerebello-thalamo-motor cortico-spinal pathways, this has not yet been accomplished. As is the case with cerebellar damage occurring in adult (Section 2.1.1) and weaning (Section 2.1.2) periods in rats, rotorod performance was impaired after lesions of VL-VM or of centrolateral intralaminar thalamus (Jeljeli et al., 2000, 2003), but the effects of lesions of the red nucleus on this and other standard tests have not been assessed. 2.2. Mutant mice with cerebellar atrophy 2.2.1. Motor coordination The genes implicated in cerebellar cortical degeneration have been identified in several ataxic models with natural mutations (Table 2). The performances on stationary beam, coat-hanger, and rotorod tests (Table 3) were deficient relative to non-ataxic controls in Grid2Lc (Hilber and Caston, 2001; Lalonde et al., 1995, 1996; Le Marec et al., 1997b; Strazielle et al., 1998), Grid2ho-Nancy (Guastavino et al., 1990; Kre´marik et al., 1998; Lalonde et al., 1995, 1996; Lalouette et al., 2001), Rorasg (Lalonde et al., 1995, 1996), and Relnrl-Orl (Lalonde

et al., 2004) mutant mice. It is possible to differentiate between motor capabilities of cerebellar mutants with these tests. In contrast to the reduced latencies before falling from the coathanger found in the four above-named mutants as well as in Agtpbp1pcd-1J (Le Marec and Lalonde, 1997), nervous mutants had normal values relative to their non-ataxic controls (Lalonde and Strazielle, 2003). These results are attributed to the relative preservation of midline Purkinje cells in nervous (Sidman and Green, 1970), unlike the other mutants. As mentioned above (Section 2.1), lesions of midline cerebellum generally lead to more severe postural deficits than those of lateral areas. Agtpbp1pcd-1J (Le Marec and Lalonde, 1997) and Grid2Lc (Lalonde et al., 1992) could be distinguished from Rorasg (Lalonde, 1987) on the basis of normal latencies before falling from a rectangular-shaped stationary beam. Although Grid2Lc and Agtpbp1pcd-1J mutants lose nearly all Purkinje cells and Rorasg 75% of them, only the latter was impaired in this test. It appears that dysfunctional Purkinje cells as a result of abnormal dendritic arborization causes poorer motor control than their total disappearance. Cerebellar mutants may also be dissociated on the basis of general ambulatory activity in an open-field or a T-maze (Table 3). While Rorasg (Deiss et al., 2000; Goodall and Gheusi, 1987; Lalonde et al., 1988) and Grid2ho (Filali et al., 1996) mutants were hypoactive relative to their respective controls, this was not the case with Grid2Lc (Caston et al., 1998; Lalonde et al., 1986b), Agtpbp1pcd (Lalonde et al., 1987), nervous (Lalonde et al., 1986a; Lalonde and Strazielle, 2003), and Relnrl-Orl (Lalonde et al., 2004) mutants. On the contrary, Grid2Lc (Caston et al., 1998; Lalonde et al., 1986b), Agtpbp1pcd (Lalonde et al., 1987), and nervous (Lalonde et al., 1986a; Lalonde and Strazielle, 2003) were hyperactive despite ataxia and frequent falls. The hypoactivity seen in Rorasg and Grid2ho is attributable to anomalies in Purkinje cell dendritic organization (Boukhtouche et al., 2006; Guastavino et al., 1990), in contrast to the severe depletion of this cell population in Grid2Lc and Agtpbp1pcd, their severe depletion in the cerebellar hemispheres in nervous, and their misalignment in Relnrl-Orl. Once again, these results imply that Purkinje cells with dysfunctional synapses lead to poorer motor control than their disappearance. Nevertheless, the rotorod performance of Grid2Lc mutants worsened after cerebellectomy (Caston et al., 1995b). Thus, after massive Purkinje and

Table 2 Main histopathological features of Grid2Lc, Grid2ho-Nancy, Rorasg, Agtpbp1pcd, nervous, and Relnrl-Orl mutant mouse cerebellum Mutation (chromosome, type) Lc

Grid2

(Chr 6, gain-of-malfunction)

Grid2ho-Nancy (Chr 6, deletion) Rorasg (Chr 9, deletion) Agtpbp1pcd-1J (Chr 13, deletion) nervous (Chr 8, unknown) Relnrl-Orl (Chr 5, deletion)

Cerebellar cell loss

Protein name

References, gene identification

Purkinje (100%), granule (>90%), deep nuclei (30%) Granule–Purkinje synaptic loss

Glutamate receptor, ionotropic, delta 2 Glutamate receptor, ionotropic, delta 2 Retinoid orphan receptor A AGTP binding protein Unknown

Zuo et al. (1997)

Reelin

Hirotsune et al. (1995)

Purkinje (75%), granule (>90%) Purkinje (100%), granule (progressive) Purkinje (midline 50%–hemisphere 90%), granule (mild) Purkinje (50%), granule (>90%), cell ectopias

Lalouette et al. (2001) Hamilton et al. (1996) Fernandez-Gonzalez et al. (2002) None

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Table 3 Latencies before falling from stationary beam, coat-hanger, and rotorod as well as motor activity in open-field or T-maze in adult Grid2Lc (Lc), Grid2ho-Nancy (ho), Rorasg (sg), Agtpbp1pcd-1J ( pcd-1J), nervous (nr), and Relnrl-Orl (rl-Orl) mutant mice Mutant

Stationary beam

Coat-hanger

Rotorod

Activity

References

,

Hilber and Caston (2001), Lalonde et al. (1986b, 1992, 1995, 1996), Le Marec et al. (1997b) and Strazielle et al. (1998) Filali et al. (1996), Kre´marik et al. (1998), Lalonde et al. (1995, 1996) and Lalouette et al. (2001) Deiss et al. (2000), Goodall and Gheusi (1987), Lalonde (1987) and Lalonde et al. (1988, 1995, 1996) Lalonde et al. (1987) and Le Marec and Lalonde (1997) Lalonde and Strazielle (2003) and Lalonde et al. (1986a) Lalonde et al. (2004)

Lc ho sg pcd-1J nr rl-Orl

, ,

The same coat-hanger was used, but some stationary beams and rotorods were different.

granule cell degeneration, remaining interneurons appeared physiologically viable in the sense of minimizing their sensorimotor disturbances. It remains to be determined whether the same pattern holds true with the other cerebellar mutants. 2.2.2. Relation between motor coordination and regional brain metabolism Further clues to the neural basis of postural deficits have been obtained by relating behavioral scores of ataxic mice with regional brain metabolism assessed by cytochrome oxidase (CO) histochemistry, a marker of neuronal activity. The rotorod score of Grid2Lc mutants was linearly correlated with CO activity in magnocellular red nucleus, a region with abnormally elevated activity of this enzyme relative to controls (Strazielle et al., 1998). This result indicates that a cerebellar output region that projects to a-motoneurons appears to take over at least in part from a dysfunctional cerebellum. The same pattern was disclosed between CO activity in medial vestibular nucleus and stationary beam performance of Rorasg mice (Deiss et al., 2000). Mutants with the highest CO activity in this region performed better on the motor test. However, the opposite pattern was seen in interpositus and dentate nuclei, where CO activity was elevated relative to controls. Indeed, CO activity in those two regions was linearly correlated with poorer stationary beam and rotorod performances. Likewise, in the Relnrl-Orl mutant, upregulated CO activity in Purkinje cells and downregulated CO activity in interpositus/dentate nuclei was correlated with poorer stationary beam performance (Lalonde et al., 2004).

: decreased;

: increased; ,: unchanged vs. non-ataxic mice.

These data indicate that motor scores of ataxic mutants can be predicted to some extent by CO activity in cerebellar-related regions. Hypermetabolism in cerebellar pathways such as red nucleus and medial vestibular nucleus is associated with finer motor control. In the opposite manner, abnormal metabolic activity in the cerebellum is associated with poorer motor performances, presumably due to local degenerative processes. 2.3. Null mutations of genes expressed in cerebellum In addition to natural mutations, information on genes involved in neuropathology has been obtained with targeted null mutations in mice, particularly for genes expressed in the cerebellum (Table 4). 2.3.1. Glutamate receptors Purkinje cells contain high levels of the ionotropic glutamate receptor delta 2 (GluRd2), whose gene is mutated in Grid2Lc (Zuo et al., 1997) and Grid2ho-Nancy (Lalouette et al., 1998). Grid2Lc represents a gain-of-malfunction mutation (Zuo et al., 1997) affecting the uptake of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors in cerebellum and its afferent/efferent pathways (Strazielle et al., 2000), while in Grid2ho-Nancy this gene is deleted (Lalouette et al., 1998). As seen with Grid2ho-Nancy mice (Kre´marik et al., 1998; Lalonde et al., 1995; Lalouette et al., 2001), the injection of a GluRd2 antibody in the subarachnoidal space above the cerebellum caused ataxia and impaired rotorod performance of adult mice (Hirai et al., 2003). Moreover, targeted Grid2 null mutants had impaired long-term depression (LTD) of Purkinje

Table 4 Motor coordination tests used in mice with targeted null mutations of genes expressed in cerebellum Gene

Protein name

Grm1 Prkcc Cntn6 Klf9 Syt4 En2

Glutamate metabotropic receptor 1 Protein kinase C, g isoform Contactin family NB-3 neural recognition molecule Basic transcription element binding protein Synaptogamin IV Engrailed-2

Tests stationary beam, rotorod stationary beam, rotorod stationary beam, rotorod, wire suspension rotorod, , stationary beam, wire suspension rotorod rotorod

: deficient vs. non-transgenic mice; ,: equivalent performance vs. non-transgenic mice.

References Aiba et al. (1994) Chen et al. (1995) Takeda et al. (2003) Morita et al. (2003) Ferguson et al. (2000) Gerlai et al. (1996)

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cells (Kashiwabuchi et al., 1995), an electrophysiologic response associated with sensorimotor learning (Ito, 1993), together with deficiencies on the rotorod and on an elevated runway with obstacles, but statistical analyses of the behavioral results were not presented (Kashiwabuchi et al., 1995). Grm1 encodes MgluR1, a subtype of metabotropic glutamate receptors abundant in Purkinje cells as well. Mice with a Grm1 null mutation were deficient on stationary beam and rotorod tests as well as LTD of Purkinje cells (Aiba et al., 1994). Although rotorod performance has been linked with LTD, these functions are pharmacologically dissociable (Welsh et al., 2005). 2.3.2. Other genes Prkcc is another gene highly expressed in Purkinje cells. The gene encodes the g isoform of protein kinase C (PKCg). Mice with a Prkcc null mutation walk with a wobbly gait and were impaired on stationary beam and rotorod tests (Chen et al., 1995). In contrast, Prkcc null mutants were not affected in regard to LTD of Purkinje cells. Expression of Cntn6 encoding the NB-3 neural recognition molecule of the contactin family increases in cerebellum up to the adult period, but progressively decreases with time in cerebrum. Cntn6 null mutants were impaired in stationary beam, rotorod, and wire suspension tests (Takeda et al., 2003). Klf9 encodes basic transcription element binding protein (BTEB) and responds to T3 thyroid hormone involved in neural development. The gene is highly expressed in cerebellar cortex, but to a more limited extent in Purkinje cells. Klf9 null mutants were impaired during acquisition of the rotorod task, but not in stationary beam and wire suspension tests and had normal activity levels in the openfield (Morita et al., 2003). Another gene highly expressed in cerebellar cortex is Syt4, encoding synaptogamin IV, a synaptic vesicle protein. Despite the absence of ataxia and normal motor activity levels, Syt4 null mutants were impaired during acquisition of the rotorod task (Ferguson et al., 2000). En2 is highly expressed in cerebellum and encodes for Engrailed-2. Mice homozygous for an En2 null mutation were compared to heterozygous and wild-type mice of the same background strain on rotorod and motor activity tests (Gerlai et al., 1996). En2/En2 and En2/+ mutants had normal activity levels and did not appear ataxic. During initial trials on the rotorod, En2/En2 mice fell sooner than the other two groups. At the end of training, En2/+ mice were impaired in comparison to +/+ but no different from the poor performing En2/En2 group. Thus, a gene dose-dependent function was obtained, homozygous mice performing worse than heterozygous and the latter in turn worse than wild-type. As mentioned in Sections 2.1 and 2.2, these results underline the particular sensitivity of the rotorod task in the detection of motor abnormalities in cerebellar-lesioned rats as well as in mice with cerebellar dysfunction irrespective of the presence of ataxia and motor activity changes.

2.4. Plasticity changes in cerebellum of normal rats and monkeys Neurochemical and morphologic changes have been described in normal cerebellum during complex movements, relative to conditions in which simpler movements were exhibited, or when rats were simply left in their home cages. For example, the mRNA expression of tissue plasminogen activator (tPA) increased in the cerebellum of rats exposed to an irregularly pegged relative to a non-pegged runway or to unexercised controls (Seeds et al., 1995). These results indicate that the molecular response associated with the initiation of complex postural adjustments include tPA. In a similar experiment, normal rats were randomly allocated to one of three conditions: (1) a rope ladder, a seesaw, and a stationary beam, permitting complex motor coordination in an obstacle course-type situation; (2) a treadmill, permitting simpler movements; or (3) an empty cage (Black et al., 1990). The exposure to the obstacle course led to higher levels of synaptogenesis in cerebellar cortex than treadmill- or home-cage conditions. In particular, the obstacle course increased the number of synapses per Purkinje cell (Kleim et al., 1997a) and the size of stellate cell dendritic trees (Kleim et al., 1997b) relative to an obstacle-free runway. The obstacle course augmented both climbing and parallel fiber synapses on Purkinje cells (Anderson et al., 1996) as well as glia per Purkinje cell (Anderson et al., 1994) relative to the treadmill condition. Purkinje dendritic tree size was also elevated in monkeys raised in a colony with toys in comparison either to isolation-reared or to social-reared monkeys without toys (Floeter and Greenough, 1979). These results complement lesion studies of the cerebellum described above. With this type of paradigm, there is a potential in uncovering which genes increase in expression in normal animals as a result of being exposed to apparatus with highlevel requirements of postural control. It is of special interest to discover whether such genes include those causing deficient motor coordination following their deletion as described in Section 2.3. 2.5. Patients with cerebellar atrophy In line with animal studies, midline cerebellar lesions cause a wide-stanced gait and frequent falls in human subjects (Dow et al., 1991). In patients with heredodegenerative ataxias, cerebellar volume was correlated with the severity of ataxic symptoms (Richter et al., 2005). Patients with cerebellar atrophy caused by heredodegenerative ataxias or by alcohol abuse with the anterior lobe (vermis and paravermis) syndrome (wide-based gait and excessive anterior/posterior sway with closed eyes) were examined on a backward-moving platform (Horak and Diener, 1994). The patients were exposed to increasing velocities at a constant amplitude or to increasing amplitudes at a constant velocity. Electromyographic (EMG) activity was recorded for six agonist-antagonist muscle pairs at the ankle, knee, and trunk. Although latencies before the appearance of agonist bursts were unaltered in cerebellar

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patients, their responses were hypermetric, with large EMG amplitudes, long burst durations, and excessive antagonist activity. The patients were able to use velocity feedback information to scale postural response magnitude, but were unable to use predictive feedforward control to scale displacement amplitudes, as if in expectation of a larger displacement than what was given. These results indicate that the midline cerebellum is critical for adjusting amplitudes of predicted movements, but not for adjusting to the velocity of forward sway, the latter being possibly mediated at brainstem or spinal levels. These data are in agreement with cerebellar involvement in the feedforward control of movement (Houk et al., 1996). Diener et al. (1984) compared patients with anterior lobe atrophy of the cerebellum to patients with Friedreich’s ataxia, a spinocerebellar disorder with sensory abnormalities in peripheral nerves and posterior columns. Three EMG responses were recorded after sudden tilting of a platform: (1) an early (50 ms) latency corresponding to the segmental stretch reflex; (2) a medium (105 ms) latency corresponding to polysynaptic spinal or extraspinal pathways and/or bursts of spindle activity; (3) a long (130 ms) latency in the antagonist of the stretched response related to stabilization of upright posture. The short-latency response could be recorded in only four of eight patients with Friedreich’s ataxia, due to disturbed proprioception. The median latency response was lengthened in patients with Friedreich’s ataxia but not in patients with anterior lobe lesions. These results indicate that spinocerebellar tracts and/or medial lemniscus are responsible for median latency responses. The long-latency response increased in patients with Friedreich’s ataxia, but not in patients with anterior lobe lesions. However, cerebellar patients had longer amplitudes and durations of antagonist responses. Thus, basic postural reflexes were impaired by cerebellar lesions. On the contrary, cerebellar patients of mixed etiology were not impaired for short-term habituation of postural responses, presumably mediated at extracerebellar levels (Schwabe et al., 2004). 2.6. Patients with lesions of cerebellar efferent regions The control of gait and posture of cerebellar-related regions mainly involves vestibular and medullary reticular nuclei projecting to axial and proximal muscles (Dow et al., 1991; Nolte, 1988). In particular, bilateral vestibular lesions in humans impaired their ability to stand up in both pitch and roll planes, with unilateral lesions causing more severe deficits for lateral sway (Mbongo et al., 2005). Patients with lesions of the ventrolateral (VL) thalamus had action tremor but with minimal gait disturbances and hypermetria (Bastian and Thach, 1995). These results indicate that the physiological role of the cerebellar-VL thalamic pathway is more closely associated with hand stability during movements than with postural control or with movement accuracy. Nevertheless, although rats with VL thalamic lesions did not lurch or totter on cursory examination, they were deficient on the rotorod (Jeljeli et al., 2003). Thus, more

53

challenging motor coordination tasks may be devised in order to gauge the possible role of thalamic nuclei in human postural control. 3. Cerebellar afferent regions Cerebellar afferents that have so far been examined with respect to motor coordination include climbing, mossy, and noradrenergic fibers (Table 1). Climbing fibers originate from the inferior olive, mossy fibers from pontine, reticular, spinal, and trigeminal nuclei (Nolte, 1988; Ruigrok, 2004; Vidal and Sans, 2004; Voogd, 2004), and noradrenergic projections from the locus coeruleus (Aston-Jones, 2004). 3.1. Lesions or neurochemical modifications in adult rats Adult rats injected with 3-acetylpyridine, a neurotoxic agent causing relatively selective inferior olive lesions, were impaired during acquisition of the rotorod task (Rondi-Reig et al., 1997). These results were replicated by Gasparri et al. (2003). These authors also reported the same deficit in rats with lesions of the middle cerebellar peduncle, which comprise pontocerebellar fibers. The role of noradrenergic afferents on motor coordination in rats was investigated by intracisternal injections of 6hydroxydopamine (6-OHDA), a neurotoxic agent which depletes cerebellar and forebrain noradrenaline concentrations (Watson and McElligott, 1983). The acquisition of the pegged runway task was slowed down in 6-OHDA-injected rats. Watson and McElligott (1984) and Bickford et al. (1992) found the same result after selective 6-OHDA injections in the coeruleo-cerebellar pathway. Heron et al. (1996) compared different noradrenergic receptor antagonists: propranolol (b receptor), prazosin (a1 receptor), and yohimbine (a2 receptor) on irregularly spaced hurdles. Propranolol slowed down acquisition but did not affect the final performance of the locomotor task. On the contrary, prazosin or yohimbine caused no impairment at all. These data implicate a role for cerebellar b noradreneric receptors in sensorimotor learning. None of the drugs impaired stationary beam performance without the hurdles. 3.2. Lesions during rat development A single study has been reported concerning the role of the inferior olive on postural control during the developmental period (Jones et al., 1995). Rats were injected with 3acetylpyridine on P15, when climbing fibers normally reach Purkinje cells, and evaluated on the rotorod from P23. Rats with inferior olive lesions were impaired in this task relative to those injected with the saline vehicle. 4. Basal ganglia The basal ganglia integrate neocortical input with respect to motor, cognitive, and emotional functions via the thalamus, which in turn project the information back to specific

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neocortical subregions (Graybiel et al., 1994; Hisoka, 1991). The effects of lesions of the basal ganglia in tasks requiring balance and equilibrium have not been so extensively investigated as those of the cerebellum. 4.1. Surgical or neurochemical lesions of rat basal ganglia The consequences of ibotenate-induced lesions of the striatum were analyzed on a stationary beam task in fooddeprived rats (Pisa, 1988). Lesions of the lateral striatum (equivalent to the putamen of primates) increased movement times but not footslips/falls. On the contrary, electrolytic lesions of the medial striatum (equivalent to the caudate of primates) had no effect on latencies before falling on the stationary beam, the suspended wire, and the rotorod in rats (Thullier et al., 1996a,b). These results are explainable by the predominance of afferent input from motor and premotor cortex to putamen but not to caudate nucleus (Nolte, 1988). Electrolytic lesions of the lateral pallidum (equivalent to the external globus pallidus of primates and interface region between striatum and motor thalamus) reduced falling latencies from the rotorod and from the stationary beam but not from the suspended wire (Jeljeli et al., 1999). These results indicate a specific involvement of the lateral pallidum on motor coordination rather than on muscle strength, which is more particularly measured on the suspended wire test, where the rat must bear its own body weight. 4.2. Dopamine depletion in rat or mouse striatum Striatal dopamine depletion induced by unilateral 6-OHDA administration in the nigro-striatal tract caused rotorod disturbances in mice (Nash et al., 2005). The same deficit was found after subcutaneous injections of methyl-phenyltetrahydroyridine (MPTP) in mice (Rozas et al., 1998). However, the effects of this dopamine-depleting compound are dose-dependent, as rotorod performance was unchanged after low dose subcutaneous injections of MPTP in mice (Tillerson et al., 2002). Dopamine depletion in the striatum has also been shown to impair reaching movements in rats (Sabol et al., 1985; Whishaw et al., 1986).

4.3. Genetically modified mice 4.3.1. Synucleinopathies Parkinson’s disease is characterized by degeneration of substantia nigra pars compacta, depleted forebrain dopamine concentrations, muscle rigidity, slowed movements, resting tremor, and postural deficits (Marsden, 1989). Although Parkinson’s disease is usually observed in the sporadic form, clues to its pathogenesis have been obtained with the discovery of missense A30P and A53T mutations of SNCA, located on Chr 4 and encoding a-synuclein (Kruger et al., 1998; Polymeropoulos et al., 1997). The a-synuclein protein is normally localized at synapses (Kahle et al., 2000) and is the main constituent of the Lewy body, histologic marker in the brain of patients with Parkinson’s disease and with dementia with Lewy bodies (DLB) (Spillantini et al., 1997). Transgenic murine models of autosomal dominant Parkinson’s disease include A30P and A53T mutations or wild-type expression of human SNCA, as well as an artificial (non-related to human disease) double mutation as seen in Table 5. A30PSNCA/Prp/mo mice accumulate human a-synuclein in forebrain, but, unlike the human disease, tyrosine hydroxylase staining was unchanged in substantia nigra and in striatum (Yavich et al., 2005). Nevertheless, as expected from a Parkinson model, A30PSNCA/Prp mice were impaired on the rotorod and hypoactive in the open-field relative to nontransgenic controls. However, the transgenic line was not affected for latencies before turning upward on the vertical grid. These results indicate that motor dysfunctions can occur after a-synuclein accumulation and before the onset of nigro-striatal degeneration. However, despite accumulation of human asynuclein, a different A30PSNCA/Prp/mo model was not affected in the rotorod test (Lee et al., 2002). A similar construct with the hamster Prp promoter was examined on two versions of the rotorod test (Gomez-Isla et al., 2003). As a result of widespread human a-synuclein accumulation, A30PSNCA/Prp/ha mice developed severe neurologic deficits, such as dystonia and paralysis, that are not part of Parkinson’s disease or DLB symptomatology. Unlike the human diseases, there was no difference in cell counts for tyrosine hydroxylase-immunoreactive cells in substantia nigra pars

Table 5 Motor coordination testing in mice overexpressing mutated or wild-type SNCA encoding synuclein Transgene manipulation

Promoter

Tests

References

A30P mutation A30P mutation A30P mutation A53T mutation A53T mutation A53T mutation G88C + G209A mutation Wild-type Wild-type Wild-type Wild-type

Mouse Prp Mouse Prp Hamster Prp Mouse Prp Mouse Prp Mouse Thy1 Rat Th Rat Th Mouse Thy1 Human PDGFB Mouse MBP

rotorod, , vertical grid , rotorod rotorod rotorod , rotorod rotorod inverted grid , inverted grid stationary beam, , inverted grid rotorod rotorod

Yavich et al. (2005) Lee et al. (2002) Gomez-Isla et al. (2003) Gispert et al. (2003) Lee et al. (2002) van der Putten et al. (2000) Richfield et al. (2002) Richfield et al. (2002) Fleming et al. (2004) Masliah et al. (2000) Shults et al. (2005)

: deficient vs. non-transgenic mice; ,: equivalent performance vs. non-transgenic mice.

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compacta. When tested before the onset of neurologic signs, A30PSNCA/Prp/ha were not impaired on the standard version of the accelerating rotorod. A deficit was demonstrated only with the unusual procedure of reversing beam rotation every 5 s. A30PSNCA/Thy1 mice accumulate aberrant human asynuclein in brainstem and spinal cord (Kahle et al., 2001). As with the A30PSNCA/Prp/ha model (Gomez-Isla et al., 2003), the A30PSNCA/Thy1 mice developed paralysis (Newmann et al., 2002). But they were unchanged with respect to dopamine concentrations in dorsal striatum and frontal cortex. Prior to paralysis, the transgenic mice were reported to be affected on the rotorod, but no statistical analysis was presented. A53TSNCA/Prp/mo mice accumulate aberrant human asynuclein in brainstem, cerebellum, and spinal cord (Lee et al., 2002). Unlike their A30PSNCA/Prp/mo model, the A53TSNCA/Prp/mo mice of these authors accumulate ubiquitin in neurons, display astrogliosis, and develop severe neurologic deficits, such as ataxia, dystonia, and paralysis. Unlike human patients, dopamine levels and dopamine transporter (DAT) density in dorsal striatum were first reported to be unchanged in the transgenic mice (Lee et al., 2002). But a more recent study (Unger et al., 2006) reveals a mild reduction in DAT density of dorsal striatum and nucleus accumbens. When assessed before the onset of neurologic signs, A53TSNCA/Prp/mo mice were hyperactive in the open-field (Unger et al., 2006), instead of the expected hypoactivity. The hyperactivity is probably due to compensatory changes in basal ganglia, as revealed by increased D1 receptor binding in substantia nigra of the transgenic mice (Unger et al., 2006). Still before the onset of neurologic signs, A53TSNCA/Prp/mo mice were examined on the rotorod, but were found to be unaffected (Lee et al., 2002). In contrast, a different A53TSNCA/Prp/mo model accumulating human a-synuclein in widespread brain regions and spinal cord had poorer performances on the rotorod than non-transgenic controls (Gispert et al., 2003). Widespread a-synuclein accumulations were observed in A53TSNCA/Thy1 mouse brain, including forebrain, brainstem, cerebellum, and spinal cord, but not in substantia nigra pars compacta (van der Putten, 2000). Relative to non-transgenic controls, A53TSNCA/Thy1 mice were impaired in the rotorod test. SNCA/Thy1 mice accumulate human wild-type a-synuclein in forebrain but without losing midbrain dopamine neurons (Rockenstein et al., 2002; Song et al., 2004). The SNCA/Thy1 mice had more footslips on the stationary beam but not on the inverted grid relative to non-transgenic controls (Fleming et al., 2004). As expected from a Parkinson model, the transgenic animals were hypoactive in the open-field. SNCA/PDGFB transgenic mice accumulate human wildtype a-synuclein in neocortex, hippocampus, and dopaminecontaining cells of substantia nigra (Masliah et al., 2000). Dopaminergic terminals were reduced in the striatum of SNCA/ PDGFB mutants. SNCA/MBP transgenic mice accumulate human wild-type a-synuclein in olygodendrocytes of basal ganglia, cerebellum, and neocortex (Shults et al., 2005). Both SNCA/PDGF-b and SNCA/MBP mice were impaired relative to their respective non-transgenic controls in the rotorod test.

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Artificially mutated SYN/Th mice were compared to human wild-type SYN/Th mice and to non-transgenic controls (Richfield et al., 2002). The mutated but not the wild-type SNCA/Th mice had reduced dopamine concentrations in striatum. However, DAT binding was not reduced in either model. The mutated but not the wild-type SNCA/Th mice had decreased activity in the open-field and higher latencies before reaching the top of an inverted grid. In summary, postural deficits have been demonstrated in several transgenic models with accumulation of a-synuclein. However, these deficits have not been specifically related to basal ganglia damage. Moreover, the deficits have not yet been shown to be improved by drugs which potentiate dopamine transmission. Unlike Parkinson and DLB symptomatology, three of the models exhibit brain and spinal cord neuropathology leading to paralysis, which nevertheless have an interest for understanding the more general role of synuclein in neurodegeneration. 4.3.2. Huntington’s disease A transgenic mouse model of Huntington’s disease was generated with the same CAG trinucleotide expansion of the HD gene as the one seen in patients (Mangiarini et al., 1996). HD transgenic mice (line R6/2) had more foot slips on the stationary beam (Carter et al., 1999) and fell sooner from the rotorod (Carter et al., 1999) than non-transgenic controls. But unlike the expected hyperactivity, HD transgenic mice were hypoactive in the open-field (Dunnett et al., 1998). 4.4. Patients with basal ganglia lesions Difficulties in postural control comprise an important symptom of Parkinson’s disease (Marsden, 1989). While compensatory changes occur as a part of normal aging in the postural stability of healthy controls, these appear less prevalent in patients with Parkinson’s disease (Bosek et al., 2005). The postural instability in these patients is manifested at the level of backward and lateral sway (Adkin et al., 2005; Horak et al., 2005). One of the underlying reasons of these postural deficits is the relative lack of anticipatory postural reflexes (Traub et al., 1988). Postural instability is at least partly due to muscle rigidity, one of the cardinal symptoms of the disease (Bartolic et al., 2005). The control of gait and posture can be partially improved with medications that potentiate dopaminergic transmission (Bartolic et al., 2005; Nallegowda et al., 2004). Amplitude and frequencies of EMG bursts of postural muscles were lessened in Parkinsonian subjects in ‘‘off’’ relative to ‘‘on’’ medication (Dick et al., 1986). Postural reflexes were compromised in a single patient with lesions of the external globus pallidus caused by respiratory acidosis, together with other Parkinsonian symptoms, such as hypophonia, micrographia, and akinesia/bradykiniesia (Kuoppamaki et al., 2005). This result is explained by the interruption of the outflow pathway from the striatum to the medial pallidum and motor thalamus via the lateral pallidum. In line with these clinical findings is the observation of postural instability on the rotorod in rats with lesions of the lateral pallidum (Jeljeli et al., 1999).

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5. Neocortex Movement-related regions at the level of the neocortex include the motor, the premotor, and the posterior parietal (Bear et al., 1996; Lawrence and Kuypers, 1968a,b). The posterior parietal cortex converts visual input into action, which is implemented in the frontal cortex by enriched two-way connections existing between the two lobes. Bilateral descending tracts from premotor cortex innervate axial and proximal muscles that are of primary importance in postural control. Electrophysiological studies indicate a role for the motor cortex in postural control of the hand in monkeys (Aflalo and Graziano, 2006). However, these studies have not been extended to whole body movements. 5.1. Surgical lesions in adult rats The effects of neocortical lesions have been investigated in adult rats running for food reward on the stationary beam (Kolb and Whishaw, 1983). The number of hindlimb misplacements increased after lesions of posterior parietal cortex, but not after lesions of motor, medial frontal, and orbitofrontal cortices. Forelimb slips were unaffected by any lesion type. The lack of a lesion effect in motor cortex underlines the particular importance of subcortical motor structures in rat postural control. It remains to be determined to what extent this result can be generalized to other tasks, especially those that affect dynamic equilibrium such as the rotorod. These data are in contrast to the impaired reaching movements seen in rats with motor cortex lesions (Bures and Bracha, 1990; Castro, 1972; Whishaw et al., 1986). They are also in contrast to increased foot slips on a horizontal grid seen in rats with sensorimotor cortex lesions, presumably due to the sensory component (Napieralski et al., 1998). The deleterious effects of posterior parietal lesions are unlikely to be mediated by a dysfunctional cerebello-thalamoparietocortical pathway (Sasaki et al., 1976; Wannier et al., 1992), as the motor cortex also receives a prominent cerebellar input via the motor thalamus (Middleton and Strick, 1998; Nolte, 1988). 5.2. Surgical lesions during rat development In contrast to the negative findings in rats lesioned and tested as adults (Kolb and Whishaw, 1983), motor cortex removal on P4 increased foot slips on the stationary beam in adult rats (Kolb and Holmes, 1983). Because this result was found only in rats with neonatal lesions, the postural deficits may be caused by abnormal neurogenesis in posterior neocortex seen after such lesions.

were compared to patients with additional damage to premotor or parietal cortex (Ustinova et al., 2001). The patients with premotor or parietal cortex lesions had poorer postural performances than those with motor cortical lesions alone. Subjects with unilateral lesions of the motor cortex were evaluated for postural adjustments during ballistic arm movements (Palmer et al., 1996). When the patients moved the unaffected arm, the associated EMG activity normally seen in contralateral back was smaller in brain-damaged patients than in controls. It would be worthwhile to repeat this experiment with whole body movements. The influence of inferior parietal-superior temporal region on postural stability was examined in patients with or without the hemispatial neglect syndrome (Pe´rennou et al., 2000). Both patient groups were impaired relative to controls, but patients with hemispatial neglect caused by unilateral lesions of the temporoparietal junction had poorer lateral stability under room lights and darkness than those without this syndrome. These results emphasize the role of posterior brain regions in the integration of visual input into stable movements, but also under conditions without visual input. 6. Conclusions The brain lesion technique in animals has helped to determine the role of cortico-subcortical structures involved in postural control. However, conclusions with respect to brain regions have often been based on a single task. In those experiments that have included multi-test batteries, taskspecific deficits have been discovered. There is a particular need in identifying specific anatomic circuits underlying each behavioral task. There is also a need in relating specific deficits to their neurochemical correlates. With the gene knockout technique, the role of specific genes on postural control has begun to be revealed. Here again, taskspecific deficits have been uncovered. There is a particular need in relating the postural deficits caused by protein deficiencies to neurotransmitters in well-defined brain regions. The analysis of patient populations has demonstrated the particular importance of the cerebellum and of the basal ganglia in postural control. However, there is a need in relating specific deficits in these brain regions to a wider range of neuroanatomic systems that include brainstem, thalamus, and neocortex. Acknowledgement This research was funded by a grant from the Natural Sciences and Engineering Research Council (NSERC) of Canada to RL.

5.3. Patients with neocortical lesions

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