Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lurcher mutants are mice with functional mutation in the 82 glutamate receptor (GluRdelta2) that is predominantly expressed in cerebellar Purkinje cells and plays a crucial role in cerebellar functions. These mice display ataxia and impaired motor-related learning tasks. In order to elucidate the role of dopaminergic receptor system in coping with mutation in delta2 glutamate receptor the behavioral effect (spatial learning) of D1 dopamine receptor activation and inhibition and changes in D1-like and D2-like dopamine receptors in striatum, hippocampus and cerebellum in C57BI/7 and C3H Lurcher mutants and wild type mice were studied. We have found that Lurcher mutants were worse in the spatial learning but mice of both types reacted similarly to D1 dopamine receptor agonist (without effect) and antagonist (worsening). Moreover, Lurchers revealed substantial higher density of both D1-like and D2-like dopamine receptors in hippocampus in C57BI/7 strain, while in C3H strain only D1-like dopamine receptors were higher. In C57BI/7 strain, D-like dopamine receptors were lower in cerebellum; D2-like dopamine receptors were not affected. In the striatum, the receptor densities were similar to the wild type counterparts. Our results suggest specific participation of dopamine receptor system in coping with olivocerebellar degeneration.
 ...
PMID:Changes of dopamine receptors in mice with olivocerebellar degeneration. 1768 27

The delta2 glutamate receptor (GluRdelta2) is predominantly expressed in Purkinje cells and plays crucial roles in cerebellar functions: GluRdelta2-/- mice display ataxia and impaired motor learning. In addition, long-term depression (LTD) at parallel fiber (PF)-Purkinje cell synapses is abrogated, and synapse formation with PFs and climbing fibers (CFs) is severely disturbed in GluRdelta2-/- Purkinje cells. Recently, we demonstrated that abrogated LTD was restored in GluRdelta2-/- Purkinje cells by the virus-mediated expression of the wild-type GluRdelta2 transgene (Tg(wt)) but not by that of mutant GluRdelta2 lacking the C-terminal seven residues to which several PDZ proteins bind (Tg(DeltaCT7)). These results indicated that the C terminus of GluRdelta2 conveys the signal(s) necessary for LTD. In contrast, other phenotypes of GluRdelta2-/- cerebellum, especially morphological abnormalities at PF and CF synapses, could not be rescued by virus-mediated transient expression. Thus, whether these phenotypes are mediated by the same signaling pathway remains unclear. To address these issues and to further delineate the function of GluRdelta2 in vivo, we generated transgenic mice that expressed Tg(DeltaCT7) on a GluRdelta2-/- background. Interestingly, although Tg(DeltaCT7) restored abnormal PF and CF synapse formation almost completely, it could not rescue abrogated LTD in GluRdelta2-/- Purkinje cells. Furthermore, although the gross motor discoordination of GluRdelta2-/- mice was restored, the cerebellar motor learning underlying delayed eyeblink conditioning remained impaired. These results indicate that LTD induction and motor learning are regulated by signaling via the C-terminal end of GluRdelta2, whereas other functions may be differentially regulated by other regions of GluRdelta2.
 ...
PMID:Differential regulation of synaptic plasticity and cerebellar motor learning by the C-terminal PDZ-binding motif of GluRdelta2. 1825 67

We present a 25-month-old female having unusual cerebellar ataxia responsive to steroid therapy. She had suddenly suffered from action tremor and trunkal ataxia, following antecedent mild respiratory infection. These symptoms lasted for a month, and therefore she was referred to our hospital. No abnormal findings were disclosed for cerebrospinal fluid or MR images, but anti-glutamate receptor delta2 antibodies were detected in serum. MR spectroscopy of the cerebellum revealed a decrease in the N-acethylasparate/creatine ratio, suggesting micro-neuronal damage. She had quickly responded to high-dose methylpredonisolone therapy and the effectiveness of this steroid was reproducible in the subsequent relapses of ataxia. This clinical course seemed to be unique and was characterized as chronic recurrent cerebellar ataxia responding to steroid therapy.
 ...
PMID:A case of chronic recurrent cerebellar ataxia responding to steroid therapy. 1855 33

The delta2 glutamate receptor (GluRdelta2) is predominantly expressed in cerebellar Purkinje cells and plays crucial roles in cerebellar functions: GluRdelta2-null mice display ataxia and impaired motor learning. Interestingly, the contact state of synapses between parallel fibers (PFs) and Purkinje cells is specifically and severely affected, and the number of normal PF synapses is markedly reduced in GluRdelta2-null Purkinje cells. Furthermore, long-term depression at PF-Purkinje cell synapses is abrogated. Cbln1, a member of the C1q/tumor necrosis factor (TNF) superfamily, is predominantly expressed and released from cerebellar granule cells. Unexpectedly, the behavioral, physiological and anatomical phenotypes of cbln1-null mice precisely mimic those of GluRdelta2-null mice. Thus, we propose that Cbln1, which is released from granule cells, and GluRdelta2, which is predominantly expressed in Purkinje cells, are involved in a common signaling pathway crucial for synapse formation/maintenance and plasticity in the cerebellum. Since molecules related to Cbln1 are expressed in various brain regions other than the cerebellum, other C1q/TNF superfamily proteins may also regulate various aspects of synapses in the CNS. Therefore, an understanding of the signaling mechanisms underlying Cbln1 and GluRdelta2 in the cerebellum will provide new insights into the roles of C1q/TNF superfamily proteins as new cytokines that regulate normal and abnormal brain functions.
 ...
PMID:New (but old) molecules regulating synapse integrity and plasticity: Cbln1 and the delta2 glutamate receptor. 1912 61

Hotfoot5J mice are spontaneously occurring ataxic mice that lack delta2 glutamate receptor (GluRdelta2) protein in cerebellar Purkinje cells. Here we aimed to rescue the ataxic phenotype of hotfoot5J mice by lentiviral vector-mediated expression of recombinant GluRdelta2 in Purkinje cells. Lentiviral vectors expressing GluRdelta2 were injected into the cerebellar cortex of hotfoot5J mice 6 or 7 days after birth, and the effects were studied on postnatal day 30. The motor behavior of hotfoot5J mice treated with vectors expressing GluRdelta2 was markedly rescued, whereas the ataxia of hotfoot5J mice treated with vectors expressing GFP was comparable to that of non-injected hotfoot5J littermates. Furthermore, the impaired release probability of glutamate from parallel fiber terminals and the failure of developmental elimination of surplus climbing fibers from Purkinje cells in hotfoot5J mice were completely rescued by GluRdelta2 expression. These results indicate the therapeutic potential of viral vector-based gene therapy for hereditary cerebellar ataxia and other neuronal disorders.
 ...
PMID:Lentiviral vector-mediated rescue of motor behavior in spontaneously occurring hereditary ataxic mice. 1957 99

The delta2 glutamate receptor (GluRdelta2) is expressed predominantly in cerebellar Purkinje cells. GluRdelta2 knock-out mice show impaired synaptogenesis and loss of long-term depression (LTD) at parallel fiber/Purkinje cell synapses, and persistent multiple climbing fiber (CF) innervation of Purkinje cells, resulting in severe ataxia. To identify domains critical for GluRdelta2 function, we produced various GluRdelta2 deletion constructs. Using lentiviral vectors, those constructs were expressed in Purkinje cells of GluRdelta2-deficient mice at postnatal day (P) 6 or 7, and rescue of abnormal phenotypes was examined beyond P30. Most constructs failed to rescue the defects of GluRdelta2-deficient mice, mainly because they were not efficiently transferred to the postsynaptic sites. However, a construct carrying only the extracellular N-terminal domain (NTD) and the intracellular C-terminal domain (CTD) linked with the fourth transmembrane domain of GluRdelta2 (NTD-TM4-CTD) caused incomplete, but significant rescue of ataxia, consistent with relatively better transport of the construct to the synapses. Notably, the expression of NTD-TM4-CTD in GluRdelta2-deficient Purkinje cells restored abrogated LTD, and aberrant CF territory in the molecular layer. Although the expression of NTD-TM4-CTD failed to rescue persistent multiple CF innervation of GluRdelta2-deficient Purkinje cells, a similar construct in which only TM4 was replaced with a transmembrane domain of CD4 successfully rescued the multiple CF innervation, probably due to more efficient transport of the protein to postsynaptic sites. These results suggest that NTD and CTD are critical domains of GluRdelta2, which functions substantially without conventional ligand binding and ion channel structures.
 ...
PMID:Rescue of abnormal phenotypes in delta2 glutamate receptor-deficient mice by the extracellular N-terminal and intracellular C-terminal domains of the delta2 glutamate receptor. 1961 53

Metabotropic glutamate (mGlu) receptors have been considered potential targets for the therapy of experimental parkinsonism. One hypothetical advantage associated with the use of mGlu receptor ligands is the lack of the adverse effects typically induced by ionotropic glutamate receptor antagonists, such as sedation, ataxia, and severe learning impairment. Low doses of the mGlu2/3 metabotropic glutamate receptor agonist, LY379268 (0.25-3 mg/kg, i.p.) increased glial cell line-derived neurotrophic factor (GDNF) mRNA and protein levels in the mouse brain, as assessed by in situ hybridization, real-time PCR, immunoblotting, and immunohistochemistry. This increase was prominent in the striatum, but was also observed in the cerebral cortex. GDNF mRNA levels peaked at 3 h and declined afterwards, whereas GDNF protein levels progressively increased from 24 to 72 h following LY379268 injection. The action of LY379268 was abrogated by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.), and was lost in mGlu3 receptor knockout mice, but not in mGlu2 receptor knockout mice. In pure cultures of striatal neurons, the increase in GDNF induced by LY379268 required the activation of the mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways, as shown by the use of specific inhibitors of the two pathways. Both in vivo and in vitro studies led to the conclusion that neurons were the only source of GDNF in response to mGlu3 receptor activation. Remarkably, acute or repeated injections of LY379268 at doses that enhanced striatal GDNF levels (0.25 or 3 mg/kg, i.p.) were highly protective against nigro-striatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice, as assessed by stereological counting of tyrosine hydroxylase-positive neurons in the pars compacta of the substantia nigra. We speculate that selective mGlu3 receptor agonists or enhancers are potential candidates as neuroprotective agents in Parkinson's disease, and their use might circumvent the limitations associated with the administration of exogenous GDNF.
 ...
PMID:Activation of mGlu3 receptors stimulates the production of GDNF in striatal neurons. 1967 95

The spectrin membrane skeleton controls the disposition of selected membrane channels, receptors, and transporters. In the brain betaIII spectrin binds directly to the excitatory amino acid transporter (EAAT4), the glutamate receptor delta, and other proteins. Mutations in betaIII spectrin link strongly to human spinocerebellar ataxia type 5 (SCA5), correlating with alterations in EAAT4. We have explored the mechanistic basis of this phenotype by targeted gene disruption of Spnb3. Mice lacking intact betaIII spectrin develop normally. By 6 months they display a mild nonprogressive ataxia. By 1 year most Spnb3(-/-) animals develop a myoclonic seizure disorder with significant reductions of EAAT4, EAAT1, GluRdelta, IP3R, and NCAM140. Other synaptic proteins are normal. The cerebellum displays increased dark Purkinje cells (PC), a thin molecular layer, fewer synapses, a loss of dendritic spines, and a 2-fold expansion of the PC dendrite diameter. Membrane and expanded Golgi profiles fill the PC dendrite and soma, and both regions accumulate EAAT4. Correlating with the seizure disorder are enhanced hippocampal levels of neuropeptide Y and EAAT3 and increased calpain proteolysis of alphaII spectrin. It appears that betaIII spectrin disruption impairs synaptogenesis by disturbing the intracellular pathways selectively regulating protein trafficking to the synapse. The mislocalization of these proteins secondarily disrupts glutamate transport dynamics, leading to seizures, neuronal damage, and compensatory changes in EAAT3 and neuropeptide Y.
 ...
PMID:Targeted deletion of betaIII spectrin impairs synaptogenesis and generates ataxic and seizure phenotypes. 2023 55

Lurcher mutant mice represent a natural model of olivocerebellar degeneration. This degeneration is caused by a mutation of the gene for the delta2 glutamate receptor. Lurcher mutants suffer from cerebellar ataxia and cognitive functions deficiency as a consequence of excitotoxic apoptosis of Purkinje cells in the cerebellar cortex and a secondary decrease of granule cells and inferior olive neurons. This process finishes by the 90th day of postnatal life, but already by 14 days, the Purkinje cells are damaged and the ataxia is fully developed. Purkinje cells die by apoptosis within the first 3 weeks of life. The aim of our work was to study the development of motor functions in the course of the ontogenetic development in Lurcher mutant mice of the B6CBA strain and to compare it with wild type mice of the same strain. Mice aged 2, 3, 6, 9, and 22 weeks were used in our experiment. Motor skills were examined using four standard tests: the horizontal wire, rotating cylinder, footbridge and slanting ladder. Our findings in Lurcher mutant mice show a significant increase of motor abilities up to the sixth postnatal week and selective decrease early after this period. This improvement of motor skills is caused by the physiological development of musculature and the nervous system, probably with some contribution of plasticity of the maturing brain. The cause of the decline of these abilities immediately after the completion of the development is unknown.
 ...
PMID:Changes of motor abilities during ontogenetic development in Lurcher mutant mice. 2041 57

Animals as well as humans adapt their locomotor patterns to suit different situations. To perform smooth and stable locomotion, they coordinate not only parts of a limb but also different limbs. The cerebellum is important for sensorimotor control and plays a crucial role in intra- and inter-limb coordination. Cerebellar gait ataxia is characterized by postural deficiencies and decomposition of movements. During locomotion, the vermis and the intermediate region of the cerebellum receive information through the spinocerebellar pathways about the ongoing activities in the spinal stepping generator and the somatosensory receptors. The information is conveyed by mossy fiber afferents to Purkinje neurons via granule cells and their axons, i.e., parallel fibers. Purkinje neurons transform the mossy fiber input signals to output signals that in turn modulate activities in the brainstem descending tract neurons of the brainstem that are involved in locomotion. Further, Purkinje neurons receive enhanced climbing fiber signals during perturbed locomotion. These climbing fiber signals may induce synaptic plasticity at the parallel fiber-Purkinje neuron synapses. Long-term depression (LTD) occurs in parallel fiber-Purkinje neuron synapses and is regarded as the cellular basis for the learning mechanism of the cerebellar neuronal circuit. The activation of parallel fibers releases glutamate and nitric oxide, and the released glutamate activates the glutamate receptors in the Purkinje neurons. mGluR1, a subtype of the metabotropic glutamate receptors, is highly expressed in Purkinje neurons. In addition, delta 2 glutamate receptor is expressed in only Purkinje neurons throughout the brain. Genetically targeted mice for these glutamate receptors and/or pharmacological blocking studies have been promoted to determine the functional linkage between the molecules at the cellular level and the adaptability of locomotion at the behavioral level. This article highlights some recent advances in the understanding of the role played by the cerebellum in the adaptive control of locomotion.
 ...
PMID:[Mechanisms of locomotor control in the cerebellum]. 2106 51


<< Previous 1 2 3 4 5 Next >>