Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153640 (Cerebellum)
 1,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gamma-aminobutyric acid (GABA) and nitric oxide are two key-transmitters in cerebellar nuclei, the major output of cerebellar circuitry. The aims of this study were to investigate the effects of acute intra-cerebellar administration of ethanol (20 mM) on extra-cellular levels of GABA and on the NMDA-induced nitric oxide (NO) production using microdialysis in the rat. We also studied: (i) the effects of a pre-administration of DNQX, a specific antagonist of AMPA receptors, on NO production, (ii) the effects of a pre-administration of 7-NI (7-nitroindazole, an inhibitor of neuronal nitric oxide synthase NOS) and APV (D-2-amino-5-phosphonovaleric acid, a specific blocker of the NMDA type glutamate receptors) on the actions of alcohol/NMDA on glutamate receptors, and (iii) the in vivo interaction between DNQX, ethanol and NMDA receptor activation. We found that ethanol decreased the amount of extra-cellular GABA, and that this effect was counterbalanced by administration of tiagabine 1 mg/kg, a potent inhibitor of GAT-1 GABA transporter, given by the i.p. route. In loco administration of NMDA increased the levels of NO, as previously reported. A pre-administration of DNQX (500 microM) increased significantly the production of NO up to toxic levels, as well as ethanol administration. A pre-administration of 7-NI or APV reduced significantly the amounts of NO when NMDA and alcohol were infused simultaneously. The combination of ethanol with DNQX was associated with a marked enhancement of the concentrations of NO. The activity of GAT-1 in cerebellar nuclei and around this target, including in glial cells expressing GAT-1 activated by ambient GABA, seems to be spared by ethanol. Tiagabine could be considered as a candidate for future investigational treatments of acute ethanol-induced dysfunction of cerebellar nuclei. We found a potentiation of the production of NO when AMPA antagonists are given simultaneously to ethanol. The hypothesis of AMPA neurotoxicity, which has convincing arguments during chronic exposure, is challenged in this model of acute cerebellar nuclear toxicity of alcohol.
Cerebellum 2005
PMID:Depression of extra-cellular GABA and increase of NMDA-induced nitric oxide following acute intra-nuclear administration of alcohol in the cerebellar nuclei of the rat. 1632 78

Since Purkinje cells are the sole output neurons of the cerebellar cortex, the postsynaptic integration of excitatory and inhibitory synaptic inputs in this cell type is a pivotal step for cerebellar motor information processing. In Purkinje cells, Gi/o protein-coupled B-type gamma-aminobutyric acid receptor (GABABR) is expressed at the annuli of the dendritic spines that are innervated by the glutamatergic terminals of parallel fibers. The subcellular localization of GABABR suggests the possibility of postsynaptic interplay between GABABR and glutamate signaling. It has recently been demonstrated that GABABR indeed modulates alpha amino-3-hydroxy-5-methyl-4-isoxalone propionate-type ionotropic glutamate receptor (AMPAR)-mediated and type-1 metabotropic glutamate receptor (mGluR1)-mediated signaling. Interestingly, GABABR exerts modulatory actions not only via the classical Gi/o protein-dependent signaling cascade but also via a Gi/o protein-independent interaction between GABABR and mGluR1. In this review, we compare the physiological nature, underlying mechanisms, and possible functional significance of these modulatory actions of GABABR.
Cerebellum 2006
PMID:GABA(B) receptor-mediated modulation of glutamate signaling in cerebellar Purkinje cells. 1681 87

This review focuses on rodent models of tremor, particularly those induced by pharmacological agents. Harmaline is one of the most frequently used tremor-generating drugs and harmaline-induced tremor is regarded as a model of essential tremor. Harmaline acts on inferior olive neurons, causing enhanced neuronal synchrony and rhythmicity in the olivocerebellar system. In addition, it selectively induces cerebellar Purkinje cell death, speculatively because of excessive glutamate release from nerve terminals of the olivocerebellar system onto Purkinje cells. Systemic administration of cholinomimetics can also produce generalized tremor, and muscarinic receptors on striatal neurons are thought to be the best candidate for the tremor-generating mechanism. On the other hand, dopaminergic neurotoxins, which are used in models of parkinsonism, have yet to be used for experimental analysis of tremor, because tremors induced by dopamine depletion in rodents are less remarkable than those induced by harmaline or cholinomimetics. Recently developed gamma-aminobutyric acid (GABA)(A) receptor alpha-1 subunit knockout mice exhibit postural and kinetic tremors, and clearly reproduce the features of essential tremors. Although from a phenomenological point of view, rodent models of tremor cannot entirely mimic human tremor disorders, they have useful advantages in the analysis of pathophysiological mechanisms underlying tremor. Development of convenient and reproducible methods for evaluating rodent tremor is therefore recommended.
Cerebellum 2007
PMID:Rodent models of tremor. 1736 67

Our understanding of GABAergic and glutamatergic neurotransmission in the CNS has been greatly influenced with the discovery and subsequent investigations of the metabotropic gamma-aminobutyric acid (B) (GABA(B)) receptors. These G-protein coupled receptors mediate slow inhibitory neurotransmission and are widely expressed and distributed in the cerebellum, where they play critical roles in neuronal excitability and modulation of synaptic neurotransmission. Their function is modulated by interaction with effector ion channels, notably inwardly rectifying K(+) channels and voltage-gated Ca(2+) channels. The receptors are encoded by two distinct subunits, GABA(B1) and GABA(B2), both of which are required in order to function normally in vivo, as shown in recombinant expression systems and in GABA(B1) -/- mice. The GABA(B1) and GABA(B2) subunits exhibit overlapping distributions in the cerebellar cortex, both at pre- and postsynaptic sites, during development and adulthood. They are in particular abundant in Purkinje cells prior to synaptogenesis and throughout postnatal development. Using high-resolution immunohistochemical techniques at the electron microscopic level in combination with quantitative analysis and three-dimensional reconstructions, it has recently been demonstrated that GABA(B) receptors undergo changes in localization on the surface of Purkinje cell dendrites and spines during postnatal development in association with the establishment and maturation of excitatory synapses. Due to this dynamic regulation, the highest densities of GABA(B1) and GABA(B2) subunits occur around the glutamatergic synapses between Purkinje cell spines and parallel fibre varicosities. This review highlights recent studies that have shed further light on the subcellular localization during postnatal development and the cell surface dynamics of GABA(B) receptors.
Cerebellum 2007
PMID:Subcellular regulation of metabotropic GABA receptors in the developing cerebellum. 1751 Sep 12

Despite the apparent uniformity in cellular composition of the adult mammalian cerebellar cortex, it is actually highly compartmentalized into transverse zones, and within each zone the cortex is further subdivided into a reproducible array of parasagittal stripes. The most extensively studied compartmentation antigen is zebrin II/aldolase c, which is expressed by a subset of Purkinje cells forming parasagittal stripes. Gamma-aminobutyric acid B receptors (GABABRs) are G-protein-coupled receptors that mediate a slow, prolonged form of inhibition in many brain areas. This study examines the localization of GABABR2 in the mouse cerebellum by using whole mount and section immunohistochemistry. The data reveal that GABABR2 immunoreactivity is expressed strongly in the dendrites of a subset of Purkinje cells that form a reproducible array of transverse zones and parasagittal stripes. By using double immunostaining, the striped pattern of GABABR2 expression was shown to be identical to that revealed by anti-zebrin II and complementary to that of phospholipase Cbeta4. This finding supports previous functional studies showing that inhibitory neurotransmission is highly patterned in the cerebellar cortex.
Cerebellum 2008
PMID:Compartmentation of GABA B receptor2 expression in the mouse cerebellar cortex. 1841 71

Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the central nervous system. Its role is especially prominent in the cerebellum, where most neuron types are GABAergic. However, little is known about its function in the cerebellum of teleost fish, which is only partly homologous to its mammalian counterpart. Here, we investigated the expression and distribution of GABA, the GABA-synthesizing enzyme glutamic acid decarboxylase 65 (GAD65), and the receptor subunits GABA(Aalpha1) and GABA(B1) in the cerebellum of adult zebrafish. GABA and GAD65 presented a similar expression pattern that comprised the molecular layer, Purkinje cells and groups of presumed Golgi cells in the granular layer, both in the cerebellar corpus and valve. GABA(A) receptor subunits are principally found on fine radial fibers in the molecular layer, while GABA(B) receptor subunits localized prominently to the cell bodies of Purkinje cells in the ganglionic layer, and to their dendrites that span the molecular layer. These results are compared to the expression of the GABAergic system in the mammalian cerebellum.
Cerebellum 2008
PMID:Immunohistochemical localization of GABA, GAD65, and the receptor subunits GABAAalpha1 and GABAB1 in the zebrafish cerebellum. 1863 86

Inhibitory transmission controls the action potential firing rate and pattern of Purkinje cell activity in the cerebellum. A long-term change in inhibitory transmission is likely to have a profound effect on the activity of cerebellar neuronal circuits. However, little is known about how neuronal activity regulates synaptic transmission in GABAergic inhibitory interneurons (stellate/basket cells) in the cerebellar cortex. We have examined how glutamate released from parallel fibers (the axons of granule cells) influences postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors in stellate cells and modulates gamma-aminobutyric acid (GABA) release from these neurons. First, we found that burst stimulation of presynaptic parallel fibers changes the subunit composition of post-synaptic AMPA receptors from GluR2-lacking to GluR2-containing receptors. This switch reduces the Ca(2+) permeability of AMPA receptors and the excitatory postsynaptic potential amplitude and prolongs the duration of the synaptic current, producing a qualitative change in synaptic transmission. This switch in AMPA receptor phenotype can be induced by activation of extrasynaptic N-methyl-D: -aspartate (NMDA) receptors and involves PICK1 and the activation of protein kinase C. Second, activation of presynaptic NMDA receptors triggers a lasting increase in GABA release from stellate cells. These changes may provide a cellular mechanism underlying associative learning involving the cerebellum.
Cerebellum 2008
PMID:Long-term synaptic plasticity in cerebellar stellate cells. 1885 95

Autism is a neurodevelopmental disorder that is often comorbid with seizures. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in brain. GABA(B) receptors play an important role in maintaining excitatory-inhibitory balance in brain and alterations may lead to seizures. We compared levels of GABA(B) receptor subunits GABA(B) receptor 1 (GABBR1) and GABA(B) receptor 2 (GABBR2) in cerebellum, Brodmann's area 9 (BA9), and BA40 of subjects with autism and matched controls. Levels of GABBR1 were significantly decreased in BA9, BA40, and cerebellum, while GABBR2 was significantly reduced in the cerebellum. The presence of seizure disorder did not have a significant impact on the observed reductions in GABA(B) receptor subunit expression. Decreases in GABA(B) receptor subunits may help explain the presence of seizures that are often comorbid with autism, as well as cognitive difficulties prevalent in autism.
Cerebellum 2009 Mar
PMID:Expression of GABA(B) receptors is altered in brains of subjects with autism. 1900 45

Cerebellum, primarily believed as a subcortical somatic motor center, is increasingly considered to be implicated in visceral activities. However, little is known about its regulation on gastrointestinal organs. In this research, we investigated the aggravated effect of microinjection of gamma-aminobutyric acid receptor subtype B (GABA(B)R) agonist, Baclofen into cerebellar fastigial nucleus (FN) on stress gastric mucosal damage (SGMD) and its possible regulatory mechanism. The gastric mucosal damage index was chosen to indicate the severity of gastric mucosal injure. Immunohistochemistry and transferase-mediated dUTP-biotin nick-endlabeling (TUNEL) methods were used to detect the variations of lateral hypothalamic area (LHA) and gastric mucosa. It had been demonstrated that FN participates in regulation of SGMD via its GABA(B)R and GABA neural pathway, which passes through the decussation of superior cerebellar peduncle and projects to the GABA receptors in LHA. Meanwhile, celiac sympathetic nerve involves in this process via mediating neural discharge, which results in the decrease of gastric mucosal blood flow. Additionally, apoptosis, proliferation and oxidation in gastric mucosa, and gastric acid contribute in the mechanism. It could be expected that these results might suggest insights to the cerebellar and hypothalamic function, and the treatment of gastrointestinal diseases.
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PMID:Lateral hypothalamic area mediated the aggravated effect of microinjection of Baclofen into cerebellar fastigial nucleus on stress gastric mucosal damage in rats. 2224 Jan 2

Flumazenil is a specific, reversibly bound antagonist at benzodiazepine binding sites of gamma-aminobutyric acid A receptors; these sites can be imaged using positron emission tomography with 11C-flumazenil. We reported an exponential decline of flumazenil volume of distribution (proportional to receptor binding) of gamma-aminobutyric acid A receptors in children 2 to 17 years. Six newborns (33.3-46.7 weeks' postconception) were studied. All had experienced epileptic seizures and undergone 60-minute dynamic 11C-flumazenil-positron emission tomography imaging after injection of 0.4 mCi/kg of 11C-flumazenil. All newborns were scanned during their natural sleep. Binding potential (indicating flumazenil receptor binding) was calculated using Logan-plot analysis. Visual and quantitative analyses showed highest receptor binding in the amygdala-hippocampus region, sensory-motor cortex, thalamus, brainstem and basal ganglia, in that order. Cerebellum and most of the cerebral cortex showed relatively low binding. This is the first demonstration of gamma-aminobutyric acid A receptor binding in human neonates and is strikingly different from that in older children/adults, showing a programmed pattern of expression. The ontogeny data of flumazenil receptor binding from children may contribute to understanding regional differences in synaptic plasticity and improve rational therapeutic use of drugs acting at the gamma-aminobutyric acid A receptor in the pediatric population.
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PMID:GABA(A) receptor imaging with positron emission tomography in the human newborn: a unique binding pattern. 2366 71


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