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Myelin is essential for efficient signal transduction in the nervous system comprising of multiple proteins. The intricacies of the regulation of the formation of myelin, and its components, are not fully understood. Here, we describe the characterization of a novel myelin basic protein (Mbp) mutant mouse, mbp(jive), which spontaneously occurred in our mouse colony. These mice displayed the onset of a shaking gait before 3 weeks of age and seizure onset before 2 months of age. Due to a progressive increase of seizure intensity, mbp(jive) mice experienced premature lethality at around 3 months of age. Mbp mRNA transcript or protein was undetectable and, accordingly, genetic analysis demonstrated a homozygous loss of exons 3 to 6 of Mbp. Peripheral nerve conductance was mostly unimpaired. Additionally, we observed grave structural changes in white matter predominant structures were detected by T1, T2 and diffusion weighted magnetic resonance imaging. We additionally observed that Mbp-deficiency results in an upregulation of Qkl, Mag and Cnp, suggestive of a regulatory feedback mechanism whereby compensatory increases in Qkl have downstream effects on Mag and Cnp. Further research will clarify the role and specifications of this myelin feedback loop, as well as determine its potential role in therapeutic strategies for demyelinating disorders., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Modern molecular genetics create a rapidly growing number of mutant mouse lines, many of which need to be phenotyped behaviorally. Poor reliability and low efficiency of traditional behavioral tests have prompted the development of new approaches to behavioral phenotyping, such as fully automated analysis of behavior in the homecage., New Method: We asked whether the analysis of spontaneous behavior during the first week in the social homecage system IntelliCage could provide useful prescreening information before specialized and time consuming test batteries are run. To determine how much behavioral variation is captured in this data, we performed principal component analysis on free adaptation data of 1552 mice tested in the IntelliCage during the past years. We then computed individual component scores to characterize and compare groups of mice., Result: We found 11 uncorrelated components which accounted for 82% of total variance. They characterize frequency and properties of corner visits and nosepokes, drinking activity, spatial distribution, as well as diurnal time course of activity. Behavioral profiles created using individual component scores were highly characteristic for different inbred strains or different lesion models of the nervous system. They were also remarkably stable across labs and experiments., Comparison With Existing Methods: Monitoring of mutant mice with known deficits in hippocampus-dependent tests produced profiles very similar to those of hippocampally lesioned mice., Conclusions: Taken together, our results suggest that already the monitoring of spontaneous behavior during a week of free adaptation in the IntelliCage can contribute significantly to high throughput prescreening of mutant mice., (Copyright © 2014 Elsevier B.V. All rights reserved.)

As part of the RIKEN large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis project, we screened mice with a dominant mutation that exhibited abnormal behavior using an open-field test and a home-cage activity test. We tested 495 male progeny of C57BL/6J males treated with ENU and untreated C3H/HeJ females using the open-field test and isolated behavioral mutant M101736, which exhibited a significant increase in spontaneous locomotor activity. We identified a missense mutation in the Tuba1 gene, which encodes the TUBA1 protein, and designated the mutant gene Tuba1(Rgsc1736). This mutation results in an aspartic acid to glycine substitution in the TUBA1 protein. Detailed analyses revealed that Tuba1(Rgsc1736) heterozygotes exhibited inattention to novel objects and aberrant patterns of home-cage activity. The results of a behavioral pharmacological analysis using methylphenidate and morphological analyses of embryonic and adult brains suggested that Tuba1(Rgsc1736) is a novel animal model for neurodevelopmental disorders., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Human vestibular dysfunction is an increasing clinical problem. Degeneration or displacement of otoconia is a significant etiology of age-related balance disorders and Benign Positional Vertigo (BPV). In addition, commonly used antibiotics, such as aminoglycoside antibiotics, can lead to disruption of otoconial structure and function. Despite such clinical significance, relatively little information has been compiled about the development and maintenance of otoconia in humans. Recent studies in model organisms and other mammalian organ systems have revealed some of the proteins and processes required for the normal biomineralization of otoconia and otoliths in the inner ear of vertebrates. Orchestration of extracellular biomineralization requires bringing together ionic and proteinaceous components in time and space. Coordination of these events requires the normal formation of the otocyst and sensory maculae, specific secretion and localization of extracellular matrix proteins, as well as tight regulation of the endolymph ionic environment. Disruption of any of these processes can lead to the formation of abnormally shaped, or ectopic, otoconia, or otoconial agenesis. We propose that normal generation of otoconia requires a complex temporal and spatial control of developmental and biochemical events. In this review, we suggest a new hypothetical model for normal otoconial and otolith formation based on matrix vesicle mineralization in bone which we believe to be supported by information from existing mutants, morphants, and biochemical studies.

The horizontal and vertical vestibulo ocular reflex (VOR) of head tilted (het) mutant mice was compared to C57BL/6 controls. Eye movements were recorded in darkness using a temporarily attached search coil. Contributions of semicircular canal versus otolith organ signals were investigated by providing a canal only (vertical axis) or canal plus otolith organ (horizontal axis) stimulus. In controls, rotations that stimulated only the canals (upright yaw and on tail roll) produced accurate VOR timing during middle frequency rotations at 0.5 Hz (gain 0.27, phase error 6 degrees), and a phase advanced VOR during low frequency rotations at 0.05 Hz (0.05, 115 degrees). In het mutant mice, these rotations produced a highly attenuated VOR response and phase errors at both 0.5 Hz (0.11, 42 degrees) and 0.05 Hz (0.01, 36 degrees). In controls, rotations that stimulated both the otolith organs and semicircular canals (upright roll and on tail yaw) produced higher VOR gains overall than were elicited during vertical axis rotations, with phase accurate VOR at both 0.5 Hz (0.52, 4 degrees) and 0.05 Hz (0.34, 9 degrees). In het mutant mice, these rotations produced a highly attenuated VOR response and phase errors at both 0.5 Hz (0.14, 51 degrees) and 0.05 Hz (0.01, 43 degrees). During constant velocity rotations about an earth horizontal axis, eye velocity bias and modulation were virtually absent in het mutant mice, while robust in controls. Control mice produced compensatory ocular deviations in response to static head tilt, but responses in het mice were weak and inconsistent. These results show that het mice not only lack all aspects of otolith mediated VOR, but also are deficient in canal mediated VOR. Because semicircular canals are normal in het mice, we conclude that central neurons of the canal VOR are dependent on otolith organ signals for normal performance.

Mu and delta opioid receptors have been demonstrated to mediate supraspinal opioid antinociception. Whereas the recombinant inbred CXBK mouse is notably deficient in mu opioid receptor antinociception, binding density, and mRNA (MOR-1) levels, little is known about delta opioid receptor processes in this strain. The present study thus compared CXBK mice and their BALB/c strain progenitors with respect to delta opioid antinociception, whole-brain receptor binding levels, and mRNA (DOR-1) levels. Following intracerebroventricular injections of the selective delta1 and delta2 opioids DPDPE and [d-Ala2]deltorphin II, respectively, CXBK mice displayed relatively lower antinociception on the tail-flick test, resulting in significantly increased ED50 values for both agonists in this strain. Decreased whole-brain specific binding of [3H][d-Ala2]deltorphin II, but not [3H]DPDPE, was also observed in CXBK mice. Solution hybridization with a probe for the DOR-1 revealed increased transcript levels in the caudate-putamen, frontal cortex, and spinal cord of this strain. The present data demonstrate a deficiency in delta1 and delta2 opioid antinociception in CXBK mice concomitant with reductions in whole-brain delta2 receptor binding and regional increases in DOR-1. Whether these observations are causally related remains to be clarified., (Copyright 1998 Elsevier Science B.V.)

Peripheral-type benzodiazepine receptors (PBR) in the brain were studied in association with epileptic seizures using EL mice, an animal model of epilepsy, and DDY mice as controls. Ro 5-4864 (i.p.), a specific agonist for PBR, elicited tonic-clonic convulsions in EL mice 2.6-times more potently than in DDY mice with CD50s of 11.9 and 31.2 mg/kg for EL and DDY mice, respectively. In contrast, pentylenetetrazole (i.p.) exerted convulsant actions on EL and DDY mice in a less differential way with CD50s of 29.2 and 48.1 mg/kg for EL and DDY mice, respectively. PK 11195 (i.v.), a specific antagonist for PBR, raised seizure thresholds of EL mice at a dose of 2 mg/kg. Binding assay revealed a 50% higher density of [3H]Ro 5-4864 binding sites in the mitochondrial fraction isolated from the cerebrum of EL mice in comparison with DDY mice. Similarly, a 40% higher density of [3H]flunitrazepam binding was observed in the mitochondrial fraction of EL mice. The results support the hypothesis that PBR, particularly those associated with mitochondria, are involved in the pathogenesis of epileptic seizures in EL mice.

A gene has been described, Ped (Preimplantation embryo development), that influences the rate of cleavage of preimplantation mouse embryos. Previous studies of linkage of Ped gene phenotype (fast or slow embryo development) and H-2 haplotype (H-2b or H-2k) in backcross embryos from the C57BL/10Sn and B10.BR congenic strains have shown that the Ped gene is located in the H-2 complex, the major histocompatibility complex (MHC) of the mouse. The present study was undertaken to localize the Ped gene to a particular subregion of the H-2 complex. Analysis of the B6.K1 and B6.K2 congenic strains, which differ at only the Q subregion of the MHC, was undertaken to test whether the Ped gene is located in the Q subregion of the MHC. Qa-2 antigen expression was used as a marker for the Q subregion and fast or slow development was used to assess Ped gene phenotype in backcross embryos generated from the mating of (B6.K1 x B6.K2)F1 and B6.K1 mice. The results showed linkage of Ped gene phenotype and Qa-2 antigen expression, which strongly supports the idea that the Ped gene is located in the Q subregion of the MHC. In a further set of experiments, litter size and weight were investigated in the B6.K1 and B6.K2 mice. Pure line and reciprocal crosses were made using sires and dams of both the B6.K1 and B6.K2 genotypes. Traits measured on pups included birth weight, weaning weight and weight per day of age from birth to weaning. Litter traits measured were number born and weaned and survivability. Sex effects existed for weaning weight and weight gain per day of age. Males gained more and were heavier than female pups (P less than 0.05). Pups whose sire or dam were B6.K2 were significantly (P less than 0.05) heavier at birth than those pups whose sire or dam were B6.K1, and B6.K2 homozygous pups were significantly (P less than 0.001) heavier than all others. Litters whose dams were B6.K2 had significantly more pups at birth (P less than 0.05) than those litters whose dams were B6.K1. Results suggest that pups that are heterozygous or homozygous B6.K2 are more apt to be heavier at birth and be in larger litters suggesting that genes in the Q region of the H-2 complex are advantageous to reproductive performance.

Because of synteny between mouse chromosome 16 and human chromosome 21, murine trisomy 16 (Ts16) has been considered an animal model for Down syndrome. Indeed, previous investigations have demonstrated that action potentials of cultured dorsal root ganglion (DRG) neurons from human trisomy 21 (Down syndrome) or mouse Ts16 fetuses show increased depolarization and repolarization rates, and decreased spike duration, compared to control neurons. In order to determine the specificity of these changes, we studied the electrical membrane properties of DRG neurons in culture from trisomy 19 (Ts19) and control fetal mice, using the whole cell patch-pipette recording technique. We found no significant differences in action potential parameters and passive membrane properties between Ts19 and control neurons. These findings support the notion that the alterations previously reported in Ts16 DRG neurons are specific, and not a general consequence of genetic imbalance imposed by autosomal trisomies.

The involuntary movements resembling the serotonin (5-HT) syndrome induced by 5-HT agonist, which is composed with symptoms such as head twitch, hind leg abduction and so on, are neurochemically evaluated in the new mutant mouse, Wriggle Mouse Sagami (WMS). Ritanserin (5-HT2 antagonist) and prazosin (alpha 1-adrenergic antagonist) both inhibited the symptoms, had a decrease in the number of times they fell down and prolonged the duration of sitting up, while SCH 23390 (dopamine1 antagonist) and YM-0911-2 (dopamine2 antagonist) did not affect them. Metergoline (5-HT1 and 5-HT2 antagonist) suppressed the locomotor activity, making it difficult to determine if it ameliorated the symptoms. The concentration of a metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) was higher than control values diffusely in the CNS except in the cerebral cortex. The accumulation of 5-HTP after the administration of amino acid decarboxylase inhibitor NSD 1015 was significantly enhanced in the hypothalamus, median raphe, cerebellum and pons. An increase in 5-HT and NA was also noted in the cerebellum. GABA was increased in the striatum. In the binding assay, the number of [3H]ketanserin binding sites was increased and that of [3H]prazosin binding sites was decreased in the striata. Meanwhile, no significant difference was observed either in the number of binding sites (Bmax) or the affinity (KD) in the [3H]5-HT binding study. The number of [3H]muscimol binding sites in the cerebellum was reduced with the dissociation constant (KD) unchanged. These results suggest the involvement of 'hyperserotonergic' neural systems, possibly due to the enhanced 5-HT synthesis, in the manifestation of the involuntary movements of WMS, with noradrenergic and GABAergic modification. WMS can be a useful model to study the function of the serotonergic system in the CNS.