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)

Metabotropic glutamate receptors (mGluRs) are a family of proteins that have seven transmembrane segments and that couple to G proteins. They differ from ionotropic glutamate receptors in that they do not form ion channels but instead affect intracellular chemical messenger systems. Eight genes coding for different subtypes of mGluRs have been identified to date and numbered accordingly in the order in which the cDNAs were cloned. Based on their principal signal-transduction capabilities in recombinant expression systems and sequence similarities, the family of mGluR subtypes is subdivided into three groups. Group 1 mGluRs (consisting of mGluR1 and 5) functionally couple to phospholipase C and affect the IP3/Ca2+ signaling pathway. The subtypes of group 2 (mGluR2 and 3) and group 3 (mGluR4, 6 7 and 8) inhibit adenylate cyclase and, thereby, mediate a decrease in cAMP concentration. All mGluR subtypes are found in the cerebellar cortex with the exception of mGluR6 which is exclusively expressed in the retina. At the parallel fiber-Purkinje cell synapses mGluR1 is localized in the peri- and extra-synaptic membrane of Purkinje cells. The main focus of this review deals with the functions of this postsynaptically localized mGluR1. These functions include (i) mediation of an inward current and a slow excitatory postsynaptic potential, and (ii) a role in induction of parallel fiber-Purkinje cell long-term depression. We discuss the mechanism underlying the mGluR1-mediated postsynaptic current as well as current theories on the role of mGluR1 in parallel fiber-Purkinje cell long-term depression.
Cerebellum
PMID:Metabotropic glutamate receptors in the cerebellum with a focus on their function in Purkinje cells. 1287 70

Inferior olivary neurons receive extensive glutamatergic and GABAergic innervation. Yet, because of the membrane properties of olivary neurons these neurotransmitters can produce only small changes in the firing rates of these cells. Moreover, olivary neurons can generate spontaneous spike activity in the absence of excitatory glutamatergic input. These facts suggest that glutamate and GABA have additional roles within the olivocerebellar system beyond simply modulating single cell firing probability. Indeed, one of the characteristics of the olivocerebellar system is its ability to generate synchronous complex spike activity across populations of Purkinje cells. The pattern of synchronous activity changes rapidly, and is thought to reflect the momentary distribution of effective electrotonic coupling between olivary neurons as shaped by afferent input to the inferior olive. However, it also possible that synchronous olivocerebellar activity is the result of synchrony inherent in the afferent activity itself. The issue of the origin of complex spike synchrony, and the role of glutamatergic olivary afferents in modulating its distribution were recently studied using multiple electrode recordings from Purkinje cells. The results of these studies, reviewed here, demonstrate that synchronous complex spike activity occurs in the absence of glutamatergic (and GABAergic) input to the inferior olive, and therefore indicate that synchronization of complex spike activity primarily results from the electrotonic coupling of olivary neurons, rather than from synchronization present within their afferents. Instead of triggering synchronous discharges directly, the results suggest that the function of tonic excitatory activity is to modulate the effective coupling of spike activity between olivary neurons. Blocking glutamate within the inferior olive causes an enhancement of the normal banding pattern of complex spike synchrony, with higher synchrony among parasagittally aligned Purkinje cells and less synchrony between non-aligned cells. This is in contrast to the more uniform synchrony distribution that follows block of GABAergic olivary afferents. Thus, GABA and glutamate play critical, and complementary, roles in determining the patterns of synchronous complex spike activity that are likely central to the functioning of the olivocerebellar system.
Cerebellum 2003
PMID:Excitatory afferent modulation of complex spike synchrony. 1450 65

The cerebellum is a central organ in the control of motor learning and performance. In this respect, the cellular plasticity model systems of multiple climbing fiber elimination and long-term depression have been intensively studied. The signalling pathways involved in these plastic changes are now well understood on a molecular level and protein kinase C (PKC) activity appears to be crucially involved in both processes. Furthermore, as shown in recent studies, Purkinje cell dendritic development also critically depends on the activity of PKC. Thereby, the Ca(2+)-dependent PKC subtypes, activated by synaptic inputs through metabotropic glutamate receptors, trigger functional changes as well as long-term anatomical maturation of the Purkinje cell dendritic tree during cerebellar development at different time levels. This review summarizes these findings and forwards the hypothesis of a link between the functional mechanisms underlying LTD and the differentiation of Purkinje cell dendrites.
Cerebellum 2003
PMID:Protein kinase C: its role in activity-dependent Purkinje cell dendritic development and plasticity. 1450 70

AMPA-type glutamate receptors may transduce both neurotoxic and neurotrophic signals, basically depending on receptor subunit composition and on the extent of receptor activation. While a great deal of data are available on the mechanisms underlying the neurotoxic effects induced by AMPA receptor stimulation, much less is known about the molecular mechanisms responsible for their neurotrophic activities. This review describes the experimental evidences in favor of a neurotrophic effect of AMPA and compares the mechanisms identified and the signaling pathways involved with those relevant for the neurotrophic activities of other neurotrophins.
Cerebellum 2004
PMID:Neurotrophic effects of AMPA. 1507 61

The effect of kainate, an agonist selective for ionotropic AMPA/kainate type of glutamate receptors, on GABAA receptor subunit expression in cultured mouse cerebellar granule cells was studied using quantitative RT-PCR, ligand binding and electrophysiology. Chronic kainate treatment, without producing excitotoxicity, resulted in preferential, dose- and time-dependent down-regulation of alpha1, alpha6 and beta2 subunit mRNA expression, the expression of beta3, gamma2 and delta subunit mRNAs being less affected. The down-regulation was reversed by DNQX, an AMPA/kainate-selective glutamate receptor antagonist. A 14-day kainate treatment resulted in 46% decrease of total [3H]Ro 15-4513 binding to the benzodiazepine sites. Diazepam-insensitive [3H]Ro 15-4513 binding was decreased by 89% in accordance with very low amount of alpha6 subunit mRNA present. Diazepam-sensitive [3H]Ro 154513 binding was decreased only by 40%, contrasting >90% decrease in alpha1 subunit mRNA expression. However, this was consistent with lower potentiation of GABA-evoked currents in kainate-treated than control cells by the alpha1-selective benzodiazepine site ligand zolpidem, suggesting compensatory expression of alpha5 (and/or alpha2 or alpha3) subunits producing diazepam-sensitive but zolpidem-insensitive receptor subtypes. In conclusion, chronic kainate treatment of cerebellar granule cells selectively down-regulates oil, alpha6 and beta2 subunits resulting in altered GABAA receptor pharmacology.
Cerebellum 2004
PMID:Kainate down-regulates a subset of GABAA receptor subunits expressed in cultured mouse cerebellar granule cells. 1507 65

This paper reports the effects of pre- and perinatal exposure to delta9-tetrahydrocannabinol (THC) on expression levels of specific AMPA glutamate receptor subunits (GluR1 and GluR2/3) in the cerebellum of male and female rats. Pregnant rats were administered saline or THC from gestational day 5 (ED5) to postnatal day 20 (PD20). Expression of the GluR1 and GluR2/3 subunits of AMPA glutamate receptors was analyzed by immunohistochemistry in THC-exposed rats at three postnatal ages: PD20 (still exposed to THC) to study the direct effect of drug exposure, and PD30 and PD70 (10 and 50 days following THC withdrawal) to analyze the long-term effects of prenatal exposure. Compared to controls, pre- and perinatal THC exposure decreased the immunoreactivity levels of the GluR1 subunit in Bergmann glial cells, as well as levels of the GluR2/3 subunit in Purkinje neurons at PD20. These changes in AMPA receptor subunit levels may correlate with the decreased excitatory neurotransmission described in the cerebellum after cannabinoid treatment, which could play a significant role in the biochemical effects of THC. In addition, the reduced glutamate receptor expression observed at PD20 did not return to normal even after THC withdrawal (PD30 and PD70). The results support the idea that THC exposure during critical stages of cerebellar development may alter the glutamatergic system, not only during the drug exposure period itself but also in adults following THC withdrawal. The decreased expressions of glutamate receptors induced by developmental THC exposure could lead to functional alterations through the inhibition of glutamatergic neurotransmission, and clearly demonstrate an interaction between cannabinoids and the glutamatergic system.
Cerebellum 2004
PMID:Down-regulation of the AMPA glutamate receptor subunits GluR1 and GluR2/3 in the rat cerebellum following pre- and perinatal delta9-tetrahydrocannabinol exposure. 1523 72

The orphan glutamate receptor delta2 (GluRdelta2) is predominantly expressed in cerebellar Purkinje cells and plays a crucial role in cerebellar functions; mice that lack the GluRdelta2 gene display ataxia and impaired motor-related learning tasks. However, when expressed alone or with other glutamate receptors, GluRdelta2 does not form functional glutamate-gated ion channels nor does it bind to glutamate analogs. Therefore, the mechanisms by which GluRdelta2 participates in cerebellar functions have been elusive. Studies of mutant mice, such as lurcher, hotfoot, and GluRdelta2 knockout mice, have provided clues to the structure and function of GluRdelta2. Particularly, morphological and electrophysiological analyses of hotfoot and GluRdelta2 knockout mice have indicated a unique role of GluRdelta2 in aligning and maintaining the postsynaptic element with the presynaptic one at parallel fiber (PF)-Purkinje cell synapses. In addition, GluRdelta2 was expressed in newly formed ectopic PF-Purkinje cell synapses found after blockade of electrical activity in adult cerebellum. Moreover, application of an antibody specific for GluRdelta2's extracellular N-terminal region abrogated synaptic plasticity. These results indicate that GluRdelta2 plays a direct role in synapse formation and synaptic plasticity in adult mice. Based on these results, two hypotheses about mechanisms by which GluRdelta2 functions are proposed in this article.
Cerebellum 2004
PMID:The delta2 glutamate receptor: a key molecule controlling synaptic plasticity and structure in Purkinje cells. 1523 75

Nitric oxide is a regulatory biological substance and an important intracellular messenger that acts as a specific mediator of various neuropathological disorders. In mammals and invertebrates, nitric oxide is synthesized from L-arginine in the central and peripheral neural structures by the endothelial, neuronal and inducible enzymatic isoforms of nitric oxide synthase. Nitric oxide may affect the function of various neurotransmitter-specific systems, and is involved in neuromodulation, reproductive function, immune response, and regulation of the cerebral blood circulation. This makes nitric oxide the main candidate in brain responses to brain ischemia/hypoxia. The cerebellum has been reported to be the area of the brain that has the highest nitric oxide synthase activity and the highest concentration of glutamate and aspartate. By glutamate receptors and physiological action of nitric oxide, cyclic guanisine-5'-monophosphate may be rapidly increased. The cerebellum significantly differs with respect to ischemia and hypoxia, this response being directly related to the duration and intensity of the injury. The cerebellum could cover the eventual need for nitric oxide during the hypoxia, boosting the nitric oxide synthase activity, but overall ischemia would require de novo protein synthesis, activating the inducible nitric oxide synthase to cope with the new situation. The specific inhibitors of nitric oxide synthesis show neuroprotective effects.
Cerebellum 2004
PMID:Nitric oxide in the rat cerebellum after hypoxia/ischemia. 1568 97

NMDA receptors in cerebellum have specific characteristics that make their function and modulation different from those of NMDA receptors in other brain areas. The properties of the NMDA receptor that modulate its function: Subunit composition, post-translational modifications and synaptic localization are summarized in an accompanying article. In this review we summarize how different signaling molecules modulate the function of NMDA receptors. The function of the receptors is modulated by the co-agonists glycine and serine and this modulation is different in cerebellum than in other areas. The NMDA receptor also has binding sites for polyamines that regulate its function. Other signaling molecules that modulate NMDA receptors function are: cAMP, neurotrophic factors such as BDNF, FGF-2 or neuregulins. These and other molecules allow an interplay between NMDA receptors and other receptors for neurotransmitters that may in this way modulate NMDA receptor function. This has been reported, for example, for metabotropic glutamate receptors. The expression and function of NMDA receptor is also modulated by synaptic activity, allowing an adaptation of the receptors function to the external inputs. NMDA receptors modulate important cerebral processes. NMDA receptors in different brain areas seem to modulate different processes. Cerebellar NMDA receptors play a special role in the modulation of motor learning and coordination. This is also briefly reviewed.
Cerebellum 2005
PMID:Modulation of NMDA receptors in the cerebellum. II. Signaling pathways and physiological modulators regulating NMDA receptor function. 1614 48

There is considerable evidence that the transition metal zinc plays an important role in mammalian neural development, physiology and pathology. The most compelling evidence for a synaptic role for zinc comes from hippocampal studies: zinc is concentrated in the synaptic vesicles of some glutamatergic neurons, zinc can be released during neural activity and zinc can modulate postsynaptic GABA and glutamate receptors. The possibility that zinc is involved in cerebellar synaptic transmission is supported by the expression of specific zinc transporters (ZnT, including the synaptic vesicle transporter ZnT-3) in the cerebellar cortex. Furthermore, some subtypes of neurotransmitter receptors, expressed by cerebellar neurones, are highly sensitive to low concentrations of exogenous zinc. However there appears to be little chelatable (synaptic) zinc in the cerebellum, deletion of the ZnT-3 gene has no effect on motor phenotype and there is currently no evidence that zinc is released from cerebellar neurones to have physiological actions. Thus it is possible that the different types of zinc transporter found in the cerebellum play a neuroprotective rather than a signalling role.
Cerebellum 2005
PMID:A role for zinc in cerebellar synaptic transmission? 1632 77


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