Changes in movement and ataxic gait with development in genetically ataxic mice: a comparison with the level of cerebellar cyclic nucleotide

Spontaneous movement and ataxic gait in ataxic mice showing various pathological changes in the cerebellum were investigated according to developmental stage by the open-field method of comparison with normal mice. As the cerebellum contains relatively high levels of cyclic nucleotide, its concentrations was measured by radioimmunoassay to elucidate the correlation between spontaneous movement and ataxic gait and the neurological changes. The movements of Rolling Mouse Nagoya (RMN), Weaver and Reeler mice without Purkinje Cell Degeneration (PCD) were found to decrease at 4 and 12 weeks of age. The degree of ataxic gait worsen in RMN, was unchanged in Reeler and improved in Weaver and PCD mice. The cerebellar c-GMP concentration of ataxic mice was decreased, while no significant changes in c-AMP concentration were found in comparison with normal mice. With development, the level of cerebellar c-GMP in Weaver mice increased, but this was not apparent in RMN, Reeler or PCD mice. The results of this investigation indicated that there may be some relation between the degree of ataxic gait and the level of cerebellar c-GMP in Weaver mice.     

Changes of ataxia, spontaneous movement and the cerebellar noradrenaline system with aging in ataxic mice

Changes of cerebellar weight, spontaneous movement and ataxia with aging were investigated in Weaver and cytosine arabinoside-injected mice (Ara-C). In addition, changes of cerebellar NA and MHPG concentrations in both mice were measured by high performance liquid chromatography. Cerebellar weight increased with aging in both mice. Spontaneous movements in Weaver mice were not significantly changed, but Ara-C mice showed a decreasing tendency with aging. Ataxic gait improved with aging in Weaver mice, but not in Ara-C mice. With aging, cerebellar NA and MHPG concentrations were decreased in controls, but not in Ara-C mice. In Weaver mice, cerebellar MHPG concentration was decreased. These results suggest that NA turnover in ataxic mice is different from that in controls, but is not correlated closely with ataxia.     

Fundamental study on ataxic mice (wriggle mouse Sagami)

Wriggle mouse Sagami (WMS), a newly discovered BALB/C mouse strain, is characterized by its locomotor instability, abnormal gait pattern and neck wriggling. Although the growth of WMS mice is delayed, compared with normal BALB/C mice, the brain size corresponds to the relatively smaller body weight. In gross or histological examinations no local atrophy appears in the cerebrum, cerebellum, brain stem or spinal cord. The c-GMP level in the WMS cerebellum is decreased, but the c-AMP level is normal. The ataxic gait is not improved significantly by the administration of thyrotropin releasing hormone (TRH). These results indicate that the mechanism inducing ataxia and abnormal gait pattern in WMS may be different from those in other genetically-determined ataxic mice, e. g., Rolling mouse Nagaya (RMN), PCD, Staggerer and Reeler.     

Elevated immunoreactive-somatostatin levels in the brain of ataxic mutant mice

Immunoreactive-somatostatin (IR-SRIF) levels were investigated in the brain of 4 types of ataxic mice (Rolling Mouse Nagoya, Weaver, PCD, Staggerer) with different cerebellar pathologies. IR-SRIF concentrations (ng/mg) were found to be significantly elevated in both cerebellum and cerebrum of all ataxic mutant mice, IR-SRIF (ng/organ) was found to be increased in the cerebellum and cerebrum in Rolling Mouse Nagoya and PCD compared with control mice. The gel-filtration profile (Sephadex G-50) in the cerebellar extracts of Rolling Mouse Nagoya proved to be identical to that of control mice. Three peaks of IR-SRIF were found to be uniformly elevated in Rolling Mouse Nagoya, with the highest peak coinciding with authentic somatostatin-14. The present results suggest that elevated levels of IR-SRIF in the brain may play a role in the mechanism underlying the manifestation of ataxia in ataxic mutant mice, especially in Rolling Mouse Nagoya and PCD.     

The antiataxic mechanism of TRH in rolling mouse Nagoya: the effects of pretreatment with dopaminergic and cholinergic drugs

Antiataxic mechanisms were investigated in Rolling mouse Nagoya (RMN). The present study was to elucidate the influence of dopaminergic (pimozide, apomorphine) and cholinergic (atropine, physostigmine) drugs on the antiataxic effect of TRH. The degree of ataxic gait and spontaneous motor activities in RMN were measured by the open field method and ANIMEX-II Pretreatment with pimozide and apomorphine had no influence on the antiataxic effects of TRH, while pretreatment with physostigmine suppressed these effects and in contrast, with atropine, increased then. The increase of spontaneous motor activities after TRH injection was antagonized by pretreatment with pimozide and physostigmine, but accentuated by pretreatment with atropine. These results may indicate that the antiataxic effects of TRH are, at least partially, mediated by the cholinergic mechanism.     

Spontaneous alternation, motor activity, and spatial learning in hot-foot mutant mice

Hot-foot mutant mice, characterized by defective innervation of Purkinje cells and an ataxic gait, were less active than normal mice in a T-maze. In spontaneous alternation testing with either single or multiple trials, hot-foot mutants, contrary to normal mice, did not alternate above chance. Moreover, the mutants had a higher number of errors and higher escape latencies in a water-filled Z-maze. These results indicate that in addition to motor coordination deficits, these cerebellar mutants have deficits in spatial learning and perseverate choices of maze arms.     

Distribution and characterization of the TRH receptors in the CNS of ataxic mutant mouse

The distribution of TRH receptors in the membrane fraction of the CNS in ataxic mutant mice (C3Hf/Nem-rol and C57BL/6j-tg) was studied. TRH binding sites in cerebellum and frontal lobe of the ataxic form and the non-ataxic heterozygotes of Rolling Mouse Nagoya were decreased in comparison with the controls, whereas those in the spinal cord of Rolling Mouse Nagoya and cerebellum of Tottering Mouse were increased in the ataxic mice over the controls. Kinetic studies were performed on cerebrum and cerebellum of the different ataxic mutant mice. Such species differences in the distribution of the TRH receptors have to be considered in the action of TRH in individual ataxia cases.     

Brain D-serine and tyrosine levels in ataxic mutant mice

Summary Since D-serine occurs at high concentrations in mammalian forebrains, the brain D-serine content was analyzed in hyperkinetic and ataxic mutant mice as well as normal control mice in a search for a physiological role. The concentrations of free D-serine (nmol/g wet weight) were 392 ± 114 (mean ± S.D.), 43 ± 17 and 18 ± 8.4 in the cerebrum, brain stem and cerebellum of the BUS mouse, respectively; and 336 ± 93,58 ± 11 and 18 ± 8.5 in the cerebrum, brain stem and cerebellum of the Rolling mouse, respectively. These values were not significantly different from those for each control animal. The present results suggest that brain D-serine may not be a cause of the abnormal movements of the mutant mice. On the contrary, among many amino acids examined, tyrosine level was found to be lower in the brain stem of BUS mouse compared to the normal control animal by amino acid analysis.     

Effects of chronic administration of phencyclidine on stereotyped and ataxic behaviors in the rat

After chronic administration of Phencyclidine (PCP) to rats, a high test dose (15 mg/kg) of PCP produced increases in stereotypic and ataxic behaviors, and a lower test dose of PCP (5 mg/kg) produced decreases in these behaviors, compared to behavioral responses of control rats. Rearing behavior in rats chronically administered PCP was increased at all test doses of the drug. Rats treated chronically with 15 mg/kg PCP for 9 days showed marked increases in most of these behaviors, whereas, rats receiving 5 mg/kg PCP for 9 days showed less change in several stereotypic and ataxic behaviors. Rats receiving 10 mg/kg PCP on a once-weekly schedule also exhibited more rearing and ataxic behavioral responses after the 3rd or 4th weekly PCP injection. Chronic PCP rats did not show more stereotypic or ataxic behavior after administration of apomorphine or amphetamine than control rats. These results suggest that chronic administration of PCP augments sensitivity to the stereotypic inducing effects of high doses, and decreases sensitivity to low doses of PCP.     

Chronic L‐DOPA induces hyperactivity,normalization of gait and dyskinetic behavior in MitoPark mice

Dopamine (DA) replacement therapy continues to be the gold standard treatment for Parkinson's disease (PD), as it improves key motor symptoms including bradykinesia and gait disturbances. With time, treatment induces side effects in the majority of patients, known as L‐DOPA‐induced dyskinesia (LID), which are often studied in animals by the use of unilateral, toxin‐induced rodent models. In this study, we used the progressive, genetic PD model MitoPark to specifically evaluate bilateral changes in motor behavior following long‐term L‐DOPA treatment at three different stages of striatal DA depletion. Besides locomotor activity, we assessed changes in gait with two automated gait analysis systems and the development of dyskinetic behavior. Long‐term treatment with a moderate, clinically relevant dose of L‐DOPA (8 mg/kg) gradually produced age‐dependent hyperactivity in MitoPark mice. In voluntary and forced gait analyses, we show that MitoPark mice with severe DA depletion have distinct gait characteristics, which are normalized to control levels following long‐term L‐DOPA treatment. The cylinder test showed an age‐dependent and gradual development of bilateral LID. Significant increase in striatal FosB and prodynorphin expression was found to accompany the behavior changes. Taken together, we report that MitoPark mice model both behavioral and biochemical characteristics of long‐term L‐DOPA treatment in PD patients and provide a novel, consistent and progressive animal model of dyskinesia to aid in the discovery and evaluation of better treatment options to counteract LID.     

Behavioral characterization of mice lacking GIRK/Kir3 channel subunits

G protein-gated inwardly rectifying K(+) (GIRK/Kir3) channels mediate the postsynaptic inhibitory effects of many neurotransmitters and drugs of abuse. The lack of drugs selective for GIRK channels has hindered our ability to study their contributions to behavior. Here, we assessed the impact of GIRK subunit ablation on several behavioral endpoints. Mice were evaluated with respect to open-field motor activity and habituation, anxiety-related behavior, motor co-ordination and ataxia and operant performance. GIRK3 knockout ((-/-)) mice behaved indistinguishably from wild-type mice in this panel of tests. GIRK1(-/-) mice and GIRK2(-/-) mice, however, showed elevated motor activity and delayed habituation to an open field. GIRK2(-/-) mice, and to a lesser extent GIRK1(-/-) mice, also displayed reduced anxiety-related behavior in the elevated plus maze. Both GIRK1(-/-) mice and GIRK2(-/-) mice displayed marked resistance to the ataxic effects of the GABA(B) receptor agonist baclofen in the rotarod test. All GIRK(-/-) mice were able to learn an operant task using food as the reinforcing agent. Within-session progressive ratio scheduling, however, showed elevated lever press behavior in GIRK2(-/-) mice and, to a lesser extent, in GIRK1(-/-) mice. Phenotypic differences between mice lacking GIRK1, GIRK2 and GIRK3 correlate well with the known impact of GIRK subunit ablation on neurotransmitter-gated GIRK currents, arguing that most neuronal GIRK channels contain GIRK1 and/or GIRK2. Altogether, our data suggest that GIRK channels make important contribution to a range of behaviors and may represent points of therapeutic intervention in disorders of anxiety, spasticity and reward.     

Tyrosine hydroxylase expression and Cdk5 kinase activity in ataxic cerebellum

Ataxia has been associated with abnormalities in neuronal differentiation and migration, which are regulated by Cyclin-dependent kinase 5 (Cdk5). The cerebellum of mice lacking Cdk5 or its activator, p35, resembles those of ataxic reeler and scrambler mice, suggesting that Cdk5 may contribute to ataxic pathology. As with other ataxic mice, the pogo/pogo mouse shows aberrant cerebellar tyrosine hydroxylase (TH) expression. Since Cdk5 phosphorylates and upregulates TH expression, we sought to analyze (i) Cdk5 activity in the pogo cerebellum, which exhibits abnormal TH expression, and (ii) TH expression in the cerebellum of p35-/- and p39-/- mice, which display reduced Cdk5 activity. Interestingly, we found that increased TH expression in the pogo cerebellum coincided with reduced Cdk5 activity. However, reduced Cdk5 activity in both p35-/- and p39-/- cerebellum did not correspond to defects in TH expression. Together, these suggest that abnormal TH expression in the cerebellum might be regulated by mechanisms other than Cdk5 activity.     

Effects of a core stability exercise program on balance and coordination in children with cerebellar ataxic cerebral palsy

Objective:To evaluate the effects of a core stability exercise program on balance, coordination, and severity of ataxia in children with cerebellar ataxic cerebral palsy (CP).Methods:Forty children with cerebellar ataxic CP (mean age: 6.75±1.35 years) were randomly assigned to a control group and an intervention group for 2 months of follow-up. The control group received a standard physical therapy program three times weekly (1 h per session), while the intervention group received a core stability program for 30 min, in addition to the selected physical therapy program. Both groups were evaluated pre-treatment and post-treatment using the Scale for the Assessment and Rating of Ataxia, the Balance Error Scoring Systems scale, Bruininks-Oseretsky tests of motor proficiency, and HUMAC balance system scores.Results:We found statistically significant reductions in the severity of ataxia, as well as improved balance and coordination in both groups, with stronger effects observed in the intervention group (P<0.05).Conclusion:The core stability program can improve balance and coordination in children with cerebellar ataxic CP when incorporated with a standard physical therapy program.     

Behavioral effects of the aqueous extract of Guiera senegalensis in mice and rats

Behavioral effects of the aqueous extract of Guiera senegalensis on the central nervous system of mice and rats were investigated. Spontaneous motor activity, pentobarbital sleeping time, amphetamine-stereotyped behavior, exploratory activity and performance on treadmills (rota-rod) were evaluated. The results revealed that the aqueous extract of G. senegalensis reduced spontaneous motor activity in mice, prolonged the duration of pentobarbital sleeping time in rats and attenuated amphetamine-induced stereotype behavior in rats. The extract also decreased exploratory activity in mice and had no observable effects on motor coordination (rota-rod) at the doses tested. The results suggested that the crude aqueous extract of G. senegalensis possesses some biologically active principles that are sedative in nature.     

Hypolocomotion, anxiety and serotonin syndrome-like behavior contribute to the complex phenotype of serotonin transporter knockout mice

Although mice with a targeted disruption of the serotonin transporter (SERT) have been studied extensively using various tests, their complex behavioral phenotype is not yet fully understood. Here we assess in detail the behavior of adult female SERT wild type (+/+), heterozygous (+/-) and knockout (-/-) mice on an isogenic C57BL/6J background subjected to a battery of behavioral paradigms. Overall, there were no differences in the ability to find food or a novel object, nest-building, self-grooming and its sequencing, and horizontal rod balancing, indicating unimpaired sensory functions, motor co-ordination and behavioral sequencing. In contrast, there were striking reductions in exploration and activity in novelty-based tests (novel object, sticky label and open field tests), accompanied by pronounced thigmotaxis, suggesting that combined hypolocomotion and anxiety (rather than purely anxiety) influence the SERT -/- behavioral phenotype. Social interaction behaviors were also markedly reduced. In addition, SERT -/- mice tended to move close to the ground, frequently displayed spontaneous Straub tail, tics, tremor and backward gait - a phenotype generally consistent with 'serotonin syndrome'-like behavior. In line with replicated evidence of much enhanced serotonin availability in SERT -/- mice, this serotonin syndrome-like state may represent a third factor contributing to their behavioral profile. An understanding of the emerging complexity of SERT -/- mouse behavior is crucial for a detailed dissection of their phenotype and for developing further neurobehavioral models using these mice.     

Behavioral effects of ceruletide in Wriggle Mouse Sagami--in comparison with in Rolling Mouse Nagoya

The behavioral effects of ceruletide in Wriggle Mouse Sagami (WMS) and Rolling Mouse Nagoya (RMN) were observed in an open-field study. Ceruletide decreased the movements of both types of mice, improving the ataxic gait in WMS; however, no such improvement was observed in RMN. There may be different mechanisms underlying the ataxic manifestations in WMS and RMN.     

Dihydrotestosterone ameliorates degeneration in muscle, axons and motoneurons and improves motor function in amyotrophic lateral sclerosis model mice

Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by a progressive loss of motoneurons. The clinical symptoms include skeletal muscle weakness and atrophy, which impairs motor performance and eventually leads to respiratory failure. We tested whether dihydrotestosterone (DHT), which has both anabolic effects on muscle and neuroprotective effects on axons and motoneurons, can ameliorate clinical symptoms in ALS. A silastic tube containing DHT crystals was implanted subcutaneously in SOD1-G93A mice at early symptomatic age when decreases in body weight and grip-strength were observed as compared to wild-type mice. DHT-treated SOD1-G93A mice demonstrated ameliorated muscle atrophy and increased body weight, which was associated with stronger grip-strength. DHT treatment increased the expression of insulin-like growth factor-1 in muscle, which can exert myotrophic as well as neurotrophic effects through retrograde transport. DHT treatment attenuated neuromuscular junction denervation, and axonal and motoneuron loss. DHT-treated SOD1-G93A mice demonstrated improvement in motor behavior as assessed by rota-rod and gait analyses, and an increased lifespan. Application of DHT is a relatively simple and non-invasive procedure, which may be translated into therapy to improve the quality of life for ALS patients.     

Age, strain, and semi-chronic hydergine treatment effects on motor activity and neuronal nucleic acid-protein metabolism in male mice

This study was designed to examine the effects of Hydergine (DHET), co-dergocrine mesylate, treatment on motor activity and neuronal nucleoprotein metabolism in several motor areas of the aging rodent brain, specifically the caudate-putamen (CP), the substantia nigra (SN), and the cerebral cortex layer V (CX). Three age groups of two different strains of mice were used which represented two different aging rates: DBA/2 male mice (short lived) and C57BL/6 male mice (long lived). A representative sample of each age group was injected (IP) daily with a single dose of either DHET (1 mg/kg) or vehicle (0.9% saline) solution for one month. Total spontaneous motor activity was measured using a File apparatus to assess the functional ability of the selected brain areas. Histochemical parameters measured included the relative RNA and protein contents from a homogeneous population of neurons within each nuclei. The RNA and protein contents were assessed with a scanning microdensitometer using azure B and Coomassie staining protocols, respectively. The results of this study provide evidence that DHET does have significant effects on neuronal functioning in the motor compartments studied at the behavioral as well as the histochemical level for DBA/2 male mice. The C57BL/6 strain showed parallel, but less significant, changes in the histochemical parameters and no statistical differences in motor activity. In addition, DHET treatment produced no sign of neurotoxicity within any of the brain nuclei in either strain.     

Selection for high alcohol preference drinking in mice results in heightened sensitivity and rapid development of acute functional tolerance to alcohol's ataxic effects

Propensity to develop acute functional (or within session) tolerance to alcohol (ethanol) may influence the amount of alcohol consumed, with higher drinking associated with greater acute functional tolerance (AFT). The goal of this study was to assess this potential correlated response between alcohol preference and AFT in second and third replicate lines of mice selectively bred for high (HAP2 and HAP3) and low (LAP2 and LAP3) alcohol preference drinking. Male and female mice were tested for development of AFT on a static dowel task, which requires that animals maintain balance on a wooden dowel in order to prevent falling. On test day, each mouse received one (1.75 g/kg; Experiment 1) or two (1.75 and 2.0 g/kg; Experiment 2) injections of ethanol; an initial administration before being placed on the dowel and in Experiment 2, an additional administration after the first regain of balance on the dowel. Blood samples were taken immediately after loss of balance [when blood ethanol concentrations (BECs) were rising] and at recovery (during falling BECs) in Experiment 1, and after first and second recovery in Experiment 2. It was found that HAP mice fell from the dowel significantly earlier and at lower BECs than LAP mice following the initial injection of ethanol and were therefore more sensitive to its early effects. Furthermore, Experiment 1 detected significantly greater AFT development (BECfalling ? BECrising) in HAP mice when compared with LAP mice, which occurred within ～30 min, supporting our hypothesis. However, AFT was not different between lines in Experiment 2, indicating that ～30–60 min following alcohol administration, AFT development was similar in both lines. These data show that high alcohol drinking genetically associates with both high initial sensitivity and very early tolerance to the ataxic effects of ethanol.