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Query: UMLS:C0153640 (Cerebellum)
 1,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polyamines regulate cell division in developing brain. Neuronal membranes and the NMDA receptor have polyamine binding or functional sites. We have visualized [3H]spermidine binding in human cerebellum sections. Autoradiographs showed high specific [3H]spermidine binding in granule cell layer and low binding in molecular layer in neonate, infant and adult cerebellum which qualitatively resembled NMDA binding. Cerebellum from neonates and infants below 6 months had a further zone of dense [3H]spermidine binding in the external granule layer of migratory cells. This second zone may show a polyamine regulatory site for cerebellar development from fetal life to early infancy.
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PMID:A polyamine binding site labelled with [3H]spermidine in developing human cerebellum. 781 95

Granule cells of the cerebellum constitute the largest homogeneous neuronal population of mammalian brain. Due to their postnatal generation and the feasibility of well characterized primary in vitro cultures, cerebellar granule cells are a model of election for the study of cellular and molecular correlates of mechanisms of survival/apoptosis and neurodegeneration/neuroprotection. The present review mainly deals with recent data on mechanisms and factors promoting survival or apoptotic elimination of cerebellar granule neurons, with a particular focus on the molecular correlates at the level of gene expression and induction of cellular signal pathways. The in vivo development is first analysed with particular reference to the role played by several neurotrophic factors and by the NMDA subtype of glutamate receptor. Then, mechanisms of survival/apoptosis are examined in the model of primary in vitro cultures, where the role of neurotrophins acting on cerebellar granule cells is followed by the large deal of data coming from the paradigm of potassium/serum withdrawal. The role of some key genes of the Bcl family, of some kinase systems and of transcriptional factors is primarily highlighted. Furthermore, the involvement of mitochondria, free radicals and proteases of the caspase family is considered. Finally, the use of cerebellar granule neurons in primary culture to experimentally address the issue of neurodegeneration and pharmacological neuroprotection is considered, with some comments on models at the borderline between necrosis and apoptosis, such as the excitotoxic neuronal damage. The overlapping of cellular signal pathways activated in granule neurons by apparently unrelated stimuli, such as neurotrophins and neurotransmitters/neuromodulators is stressed to put into light the special 'trophic' role played by activity in neurons. Finally, the advantage of designing and performing conceptually equivalent experiments on cerebellar granule neurons during development in vivo and in vitro, is stressed. On the basis of the reviewed material, it is concluded that cerebellar granule neurons have acquired a special position in modern neuroscience as one of the most reliable models for the study of neural development, function and pathology.
Cerebellum
PMID:Cerebellar granule cells as a model to study mechanisms of neuronal apoptosis or survival in vivo and in vitro. 1287 73

The classically conditioned eyeblink reflex is the best studied model for understanding the neural mechanisms that underlie learning and memory. Here, data from an in vitro model of the conditioned eyeblink reflex are summarized with the aim of shedding some light on potential cellular mechanisms that may underlie eyeblink classical conditioning. An isolated brainstem-cerebellum preparation from turtles was developed in which to study the synaptic circuitry of pathways involving the cerebellum, red nucleus and brainstem nuclei. A neural correlate of an eyeblink response recorded in the abducens nerve can be conditioned entirely in vitro by pairing trigeminal and auditory nerve stimulation. Conditioned abducens nerve responses (CRs) are not generated or sustained by unpaired stimuli and their long latencies, on the order of hundreds of milliseconds, support the interpretation that the CRs are not unconditioned responses. Ablation experiments show that CRs can be generated in brainstem preparations lacking a cerebellum or the medulla. However, the timing of the CRs are disrupted by removal of the cerebellar circuitry. Thus, a highly reduced in vitro brainstem preparation demonstrates acquisition of CRs but poor timing features. Recent experiments have focused on elucidating cellular mechanisms for CR acquisition in the brainstem blink circuitry. These studies show that NMDA-mediated synaptic mechanisms are required to generate CRs and that the level of conditioning is associated with the upregulation of GluR4-containing AMPA receptors in the abducens motor nuclei. Data from immunocytochemistry and physiological experiments using the calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 suggest that CaMKII does not have a key role in mediating the induction or expression of abducens nerve CRs. It is hypothesized that GluR4-containing AMPA receptors in the abducens motor nuclei are targeted to auditory nerve synapses by an NMDA receptor-dependent process to strengthen the CS input during conditioning which results in the generation of CRs. Future studies will examine the synaptic localization of GluR4 and potential signal transduction pathways involved in in vitro conditioning. Moreover, the role feedback loops through the cerebellum and their role in CR timing will be a key issue to address using this preparation.
Cerebellum 2003
PMID:In vitro classical conditioning of the turtle eyeblink reflex: approaching cellular mechanisms of acquisition. 1288 35

The confirmed pharmacological treatment of cerebellar ataxia is still lacking. In a recent preliminary trial, we showed that D-cycloserine, a partial NMDA allosteric agonist, may relieve the symptoms. In this paper, major clinical trials to relieve ataxic symptoms are reviewed. Previous studies showed some efficacy of physostigmine in ataxic patients. However, physostigmine did not improve the ataxia in a recent double-blind crossover study. The replacement therapy of the deficient cholinergic system with choline or choline derivatives was tried in patients with Friedreich's ataxia and other ataxic patients, but the result was not definitive. A levorotatory form of hydroxytryptophan (a serotonin precursor), a serotoninergic 5-HT1A agonist, a serotoninergic 5-HT3 antagonist, and a serotonin reuptake inhibitor were also used for the therapy for ataxia. In a double-blind randomized study, buspirone, a 5-HT1A agonist was active in cerebellar ataxia, but the effect is partial and not major. The effects of the studies with the other serotoninergic drugs were not consistent. The effect of sulfamethoxazole-trimethoprim therapy in spinocerebellar ataxia type3/Machado-Joseph disease (MJD) was reported, although the therapy improved spasticity or rigidity, rather than ataxia. In contrast to previous studies, sulfamethoxazole-trimethoprim therapy in MJD had no effect in a 2001 double-blind crossover study. The thyrotropin-releasing hormone, D-cycloserine, and acetazolamide for SCA6 may have some efficacy. However, a well-designed double-blind crossover trial is needed to confirm the effect.
Cerebellum 2004
PMID:Pharmacological treatments of cerebellar ataxia. 1523 78

NMDA receptors modulate important cerebral processes such as synaptic plasticity, long-term potentiation, learning and memory, etc. NMDA receptors in cerebellum have specific characteristics that make their function and modulation different from those of NMDA receptors in other brain areas. In this and the accompanying review we summarize the information available on the modulation of NMDA receptors in cerebellum. We review the properties of the NMDA receptor that modulate its function: subunit composition, post-translational modifications and synaptic localization. NMDA receptors are heteromeric ligand-gated ion channels assembled from two families of subunits, NR1 and NR2. There are at least eight splicing variant isoforms of the NR1 subunit and four types of NR2 subunits: NR2A, NR2B, NR2C and NR2D. NMDA receptors with different subunit composition or different splice variants of NR1 subunit have different properties. The expression of the different subunits and splicing variants varies during development. Two special characteristics of NMDA receptors in cerebellum that do not occur in other brain areas are the enrichment in the NR2C subunit and in the splice variant NR1b. As a consequence of these and other factors the pharmacology of NMDA receptors is also different in cerebellum than in other brain areas. The function and localization of NMDA receptors is also modulated by postranslational modifications including phosphorylation, glycosylation and nytrosylation. NMDA receptors are phosphorylated in serines of both NR1 and NR2 subunits and in tyrosines of NR2 subunits. Another factor modulating NMDA receptors function is the synaptic localization. The trafficking and clustering of NMDA receptors is modulated by phosphorylation and by interaction with other proteins. The signaling pathways and physiological modulators regulating NMDA receptor function as well as the role of these receptors in motor learning and coordination are reviewed in an accompanying article.
Cerebellum 2005
PMID:Modulation of NMDA receptors in the cerebellum. 1. Properties of the NMDA receptor that modulate its function. 1614 47

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

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

The cellular and synaptic organization of new born mouse cerebellum maintained in organotypic slice cultures was investigated using immunohistochemical and patch-clamp recording approaches. The histological organization of the cultures shared many features with that observed in situ. Purkinje cells were generally arranged in a monolayer surrounded by a molecular-like neuropil made of Purkinje cell dendritic arborizations. Purkinje cell axons ran between clusters of small round cells identified as granule cells by Kv3.1b potassium channel immunolabelling. The terminal varicosities of the Purkinje cells axons enwrapped presumptive neurons of the cerebellar nuclei whereas their recurrent collaterals were in contact with Purkinje cells and other neurons. Granule cell axons established contacts with Purkinje cell somata and dendrites. Parvalbumin and glutamine acid decarboxylase (GAD) immunohistochemistry revealed the presence of presumptive interneurons throughout the culture. The endings of granule cell axons were observed to be in contact with these interneurons. Similarly, interneurons endings were seen close to Purkinje cells and granule cells. Whole cell recordings from Purkinje cell somata showed AMPA receptor-mediated spontaneous excitatory post-synaptic currents (sEPSCs) and GABAA receptor-mediated spontaneous inhibitory post-synaptic currents (sIPSCs). Similar events were recorded from granule cell somata except that in this neuronal type EPSPs have both a NMDA component and an AMPA component. In addition, pharmacological experiments demonstrated a GABAergic control of granule cell activity and a glutamatergic control of GABAergic neurons by granule cells. This study shows that a functional neuronal network is established in such organotypic cultures even in the absence of the two normal excitatory afferents, the mossy fibers and the climbing fibers.
Cerebellum 2006
PMID:Synaptic organization of the mouse cerebellar cortex in organotypic slice cultures. 1713 87

In this study, we synthesized and evaluated several amino 4-hydroxy-2(1H)-quinolone (4HQ) derivatives as new PET radioligand candidates for the glycine site of the NMDA receptors. Among these ligands, we discovered that 7-chloro-4-hydroxy-3-{3-(4-methylaminobenzyl) phenyl}-2-(1H)-quinolone (12) and 5-ethyl-7-chloro-4-hydroxy-3-(3-methylaminophenyl)-2(1H)-quinolone (32) have high affinity for the glycine site (K(i) values; 11.7 nM for 12 and 11.8 nM for 32). In vitro autoradiography experiments indicated that [(11)C]12 and [(11)C]32 showed high specific binding in the brain slices, which were strongly inhibited by both glycine agonists and antagonists. In vivo brain uptake of these (11)C-labeled 4HQs were examined in normal mice. Cerebellum to blood ratio of accumulation, of both [(11)C]12 and [(11)C]32 at 30 min were 0.058, which were slightly higher than those of cerebrum to blood ratio (0.043 and 0.042, respectively). These results indicated that [(11)C]12 and [(11)C]32 have poor blood brain barrier permeability. Although the plasma protein-binding ratio of [(11)C]32 was much lower than methoxy analogs (71% vs 94-98%, respectively), [(11)C]32 still binds with plasma protein strongly. It is conjectured that still acidic moiety and high affinity with plasma protein of [(11)C]32 may prevent in vivo brain uptake. In conclusion, [(11)C]12 and [(11)C]32 are unsuitable for imaging cerebral NMDA receptors.
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PMID:Development of N-[11C]methylamino 4-hydroxy-2(1H)-quinolone derivatives as PET radioligands for the glycine-binding site of NMDA receptors. 1958 74

The cerebellar nuclei (CN) process inhibition from Purkinje cells (PC) and excitation from mossy and climbing fiber collaterals. CN neurons in slices show intrinsic pacemaking activity, which is easily modulated by synaptic inputs. Our work using dynamic clamping and computer modeling shows that synchronicity between PC inputs is an important factor in determining spike rate and spike timing of CN neurons and that brief pauses in PC inputs provide a potent stimulus to trigger CN spikes. Excitatory input can equally control spike rate, but, due to a large slow, NMDA component also amplifies responses to inhibitory inputs. Intrinsic properties of CN neurons are well suited to provide prolonged responses to strong input transients and could be involved in motor pattern generation. One such specific mechanism is given by fast and slow rebound bursting. Nevertheless, we are just beginning to unravel synaptic integration in the CN, and the outcome of the work to date is best characterized by the generation of new specific questions that lend themselves to a combined experimental and computer modeling approach in future studies.
Cerebellum 2011 Dec
PMID:Mini-review: synaptic integration in the cerebellar nuclei--perspectives from dynamic clamp and computer simulation studies. 2125 24


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