Including Motor Coordination Research Articles

Truncation of Ube3a-ATS Unsilences Paternal Ube3a and Ameliorates Behavioral Defects in the Angelman Syndrome Mouse Model

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by maternal deficiency of the imprinted gene UBE3A. Individuals with AS suffer from intellectual disability, speech impairment, and motor dysfunction. Currently there is no cure for the disease. Here, we evaluated the phenotypic effect of activating the silenced paternal allele of Ube3a by depleting its antisense RNA Ube3a-ATS in mice. Premature termination of Ube3a-ATS by poly(A) cassette insertion activates expression of Ube3a from the paternal chromosome, and ameliorates many disease-related symptoms in the AS mouse model, including motor coordination defects, cognitive deficit, and impaired long-term potentiation. Studies on the imprinting mechanism of Ube3a revealed a pattern of biallelic transcription initiation with suppressed elongation of paternal Ube3a, implicating transcriptional collision between sense and antisense polymerases. These studies demonstrate the feasibility and utility of unsilencing the paternal copy of Ube3a via targeting Ube3a-ATS as a treatment for Angelman syndrome.

The Effects of Changes in Upper Limb Loads on the Activity of the Gluteus Medius Muscle in Single Limb Support

Balance is an ability to have major effects on theperformance of all activities in daily living to main -tain the body in equilibrium(1, 2). Balance is a com -plex motor control work that include the integrationof sensory information, processing by the nervoussystem, and biomechanical factors(3). Three func -tional elements, that is, support by the muscu -loskeletal system which is the biomechanical aspectof the body, motor functions including motor coordi-nation, and integrated actions of sensory functionsare necessary for normal balance responses tooccur(4). The body can maintain balance only wheninternal force(muscle contraction, etc.) acts againstpostural changes caused by external forces(gravity,inertia, ground reaction forces, etc.)(5).The gluteus medius muscle is a representative hipjoint abductor muscle and is an important antigrav -ity muscle. This is a fan-shaped muscle extendingfrom the crista iliaca of the pelvis to the greatertrochanter of the femur which beings to contract atthe end stage of the swing phase, contracts maxi-mally during the mid stance phase. It contractsefferently to prevent the pelvis from dropping duringthe swing phase(6). If the gluteus medius muscle isweek or the beginning of hip joint abduction move -ments is suppressed, hip hiking deformation willoccur. Therefore, if the gluteus medius muscle isweakened or suppressed, walking will be damaged orrestricted(7). Patients with weak gluteus mediusmuscles cannot maintain pelvic stability, become tohave problems in walking as a results, and graduallydevelop low back pain, buttock pain, and greatertrochanter bursitis, etc. When the low back pain offemales with weak gluteus medius muscles wasidentified through physical tests and the weak glu -teus medius muscles were treated with appropriaterehabilitation programs, the pain of patients withweak gluteus medius muscles was graduallyrelieved(8). The gluteus medius muscle is maximallyactivated when the hip joint is abducted or internallyrotated. The gluteus medius muscle's isotonic abduc -tion and internal rotation movements in single limbsupport are very effective in the early stage of neu -romuscular rehabilitation. Therefore, those move -ments should be made very importantly in the earlystage of rehabilitation and rotation and functionalmovement patterns should be added to the hipjoint(9).

Rodent motor and neuropsychological behaviour measured in home cages using the integrated modular platform SmartCage™

1. To facilitate investigation of diverse rodent behaviours in rodents' home cages, we have developed an integrated modular platform, the SmartCage(™) system (AfaSci, Inc. Burlingame, CA, USA), which enables automated neurobehavioural phenotypic analysis and in vivo drug screening in a relatively higher-throughput and more objective manner. 2, The individual platform consists of an infrared array, a vibration floor sensor and a variety of modular devices. One computer can simultaneously operate up to 16 platforms via USB cables. 3. The SmartCage(™) detects drug-induced increases and decreases in activity levels, as well as changes in movement patterns. Wake and sleep states of mice can be detected using the vibration floor sensor. The arousal state classification achieved up to 98% accuracy compared with results obtained by electroencephalography and electromyography. More complex behaviours, including motor coordination, anxiety-related behaviours and social approach behaviour, can be assessed using appropriate modular devices and the results obtained are comparable with results obtained using conventional methods. 4. In conclusion, the SmartCage(™) system provides an automated and accurate tool to quantify various rodent behaviours in a 'stress-free' environment. This system, combined with the validated testing protocols, offers powerful a tool kit for transgenic phenotyping and in vivo drug screening.

Cystatin C Rescues Degenerating Neurons in a Cystatin B-Knockout Mouse Model of Progressive Myoclonus Epilepsy

In vitro studies have shown that cystatin C (CysC) is neuroprotective. Here we demonstrate that CysC is neuroprotective in vivo, in a mouse model of the inherited neurodegenerative disorder, progressive myoclonic epilepsy type 1 (EPM1). Loss-of-function mutations in the cystatin B (CysB) gene, an intracellular cysteine protease inhibitor, lead to this human disease. A CysB-knockout (CysBKO) mouse model develops symptoms that mimic EPM1. CysB deficiency in these mice results in enhanced cathepsin B and D activities, indicating lysosomal dysfunction. We show that expression of CysC is enhanced in the brains of CysBKO mice. Crossbreeding of CysBKO mice with either CysC-overexpressing transgenic mice or CysC-knockout mice demonstrates that clinical symptoms and neuropathologies, including motor coordination disorder, cerebellar atrophy, neuronal loss in the cerebellum and cerebral cortex, and gliosis caused by CysB deficiency, are rescued by CysC overexpression and exacerbated by CysC deficiency. Thus, CysC effectively rescues the CysB loss-of-function mutations, facilitating the reversal of pathophysiological changes and suggesting a novel therapeutic intervention for patients with EPM1 and other neurodegenerative disorders.

Neurocognitive Test Profiles of Extremely Low Birth Weight Five-Year-Old Children Differ According to Neuromotor Status

The neurocognitive outcome of children born with extremely low birth weight (ELBW) is highly variable due to the complexity of morbidity. So far, no study has compared comprehensive neuropsychological test profiles in groups with different neuromotor status. In a national cohort of ELBW children neuropsychological test profiles were assessed in 4 groups defined according to a neurological examination at 5 years of age: normal neuromotor status (N = 56), motor coordination problems (N = 32), multiple subtle neuromotor signs including both motor coordination problems and deviant reflexes (N = 20), and spastic diplegia (N = 12). The neurocognitive assessment included a test of intelligence, the Wechsler Primary and Preschool Scale of Intelligence–Revised (WPPSI–R) and 14 subtests of attention and executive functions, verbal functions, manual motor functions, visuoconstructional functions and verbal learning (NEPSY). The children with normal neuromotor status performed within the average range; children with motor coordination problems had widespread impairment; and children with spastic diplegia and children with multiple minor neuromotor signs had uneven test profiles with stronger verbal results but weaknesses in attention and executive functions, and in manual motor and visuoconstructional tasks. In conclusion, very preterm children with neuromotor signs, including motor coordination problems, are at risk for neurocognitive impairment, in spite of average intelligence. More impaired children have more irregular test profiles. Follow-up and neuropsychological assessment of very preterm children with minor neuromotor signs are therefore indicated.

Neurological Abnormalities in Chinese Schizophrenic Patients

Background: This study attempted to examine the prevalence and type of neurological signs in Chinese patients with schizophrenia. Methods: A cross-sectional design was adopted with the use of the Cambridge Neurological Inventory (CNI). The CNI is comprised of 7 subscales, including motor coordination, sensory integration, disinhibition, extrapyramidal signs, dyskinesia, catatonia, and pyramidal signs. The former 3 subscales were classified as soft signs, whereas the latter 4 subscales were classified as hard signs. A total of 250 Chinese schizophrenic patients and 90 normal controls were recruited. Results: Patients exhibited significantly more signs than normal controls in all subscales but pyramidal signs (p < 0.00005). Significant differences were also found in total soft signs, total hard signs as well as total neurological signs (p < 0.0005). The three subscales of soft signs showed a relatively better sensitivity and specificity as compared with the four subscales of hard signs. Improvement in sensitivity and specificity was demonstrated when the subscales were collapsed into total soft signs, total hard signs and total neurological signs. A cut-off of 4 in total soft signs yields a sensitivity of 0.63 and specificity of 0.71; whereas a cut-off of 1 in total hard signs yields a sensitivity of 0.78 and specificity of 0.89. A global cut-off of 5 in total neurological signs results in a sensitivity of 0.81 and specificity of 0.73 for detecting schizophrenia versus normal. Conclusions: High levels of neurological abnormality characterize schizophrenic patients. An extended assessment battery of CNI provides even better discrimination of patients from normal controls, and soft signs are more strongly associated with schizophrenia than are hard signs in the Chinese sample.

Altered cerebellar function in mice lacking Ca V2.3 Ca 2+ channel

Voltage-dependent Ca 2+ channels play important roles in cerebellar functions including motor coordination and learning. Since abundant expression of Ca V2.3 Ca 2+ channel gene in the cerebellum was detected, we searched for possible deficits in the cerebellar functions in the Ca V2.3 mutant mice. Behavioral analysis detected in delayed motor learning in rotarod tests in mice heterozygous and homozygous for the Ca V2.3 gene disruption (Ca V2.3+/− and Ca V2.3−/−, respectively). Electrophysiological analysis of mutant mice revealed perplexing results: deficit in long-term depression (LTD) at the parallel fiber Purkinje cell synapse in Ca V2.3+/− mice but apparently normal LTD in Ca V2.3−/− mice. On the other hand, the number of spikes evoked by current injection in Purkinje cells under the current-clamp mode decreased in Ca V2.3 mutant mice in a gene dosage-dependent manner, suggesting that Ca V2.3 channel contributed to spike generation in Purkinje cells. Thus, Ca V2.3 channel seems to play some roles in cerebellar functions.

Study on the Social Maturity, Self-Perception, and Associated Factors, Including Motor Coordination, of Children with Attention Deficit Hyperactivity Disorder

This study was designed to identify characteristics of social maturity and self-perception in children with attention deficit hyperactivity disorder (ADHD) and to elucidate associated factors, including motor coordination. The subjects were 15 children (14 boys and 1 girl, in elementary school grades 3 to 6). Their characteristics were assessed with the Movement Assessment Battery for Children (M-ABC), the Japanese version of the Social Maturity Scale-R (S-M scale), and Harter's Self Perception Profile for Children (SPPC). The results of the study suggested that most of the subjects had some degree of motor problem and delay of social maturity. They also suggested an association between social maturity and static-dynamic balance, which was one of the indices of motor coordination.

Study on the Social Maturity, Self-Perception, and Associated Factors, Including Motor Coordination, of Children with Attention Deficit Hyperactivity Disorder

This study was designed to identify characteristics of social maturity and self-perception in children with attention deficit hyperactivity disorder (ADHD) and to elucidate associated factors, including motor coordination. The subjects were 15 children (14 boys and 1 girl, in elementary school grades 3 to 6). Their characteristics were assessed with the Movement Assessment Battery for Children (M-ABC), the Japanese version of the Social Maturity Scale-R (S-M scale), and Harter's Self Perception Profile for Children (SPPC). The results of the study suggested that most of the subjects had some degree of motor problem and delay of social maturity. They also suggested an association between social maturity and static-dynamic balance, which was one of the indices of motor coordination.

Neonatal choline supplementation ameliorates the effects of prenatal alcohol exposure on a discrimination learning task in rats

Prenatal alcohol exposure can disrupt brain development and lead to a myriad of behavioral alterations, including motor coordination deficits, hyperactivity, and learning deficits. There remains a need, however, to identify treatments and interventions for reducing the severity of alcohol-related neurodevelopmental disorders. Some of the alcohol-induced deficits in learning may be related to alterations in cholinergic functioning. Interestingly, there is a growing literature demonstrating that pre- and/or early postnatal choline supplementation can lead to long-term enhancement in learning and memory and cholinergic activity in rats. The present study examined whether such early choline supplementation might counter the effects of prenatal alcohol treatment on a visuospatial discrimination task. Pregnant Sprague–Dawley rats were randomly assigned to one of three prenatal treatment groups. One group received a liquid diet containing 35% ethanol-derived calories (EDC) from gestational day (GD) 6–20. A second group served as a pair-fed (PF) control group and the third group served as an ad lib lab chow (LC) control. On postnatal day (PD) 2, pups were assigned within-litter to one of three postnatal treatments: choline, saline vehicle, or no treatment. Choline and vehicle pups were intubated with a choline chloride solution or vehicle daily from PD 2 to 21, whereas the non-treated pups were handled daily but not intubated. On PD 45, subjects were tested on a visuospatial discrimination task. Ethanol-exposed subjects who were not treated neonatally with choline committed a significantly greater number of errors both during acquisition and during delayed discrimination training compared to both PF and LC controls. Neonatal choline treatment significantly improved performance on the discrimination task in all groups; however, the beneficial effects of choline were significantly larger in ethanol-exposed subjects. Indeed, the performance of ethanol-exposed pups treated with neonatal choline did not differ from any of the PF or LC groups on any measure. Thus, early postnatal choline supplementation significantly attenuated the effects of prenatal alcohol on this learning task. Importantly, these effects were not due to the acute effects of choline, but rather to long-term changes in brain and behavioral development. These data suggest that early dietary interventions may reduce the severity of fetal alcohol effects.