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PubMed2002

HRP injection in lobule VI-VII of the cerebellar cortex reveals a bilateral inferior olive projection in granuloprival rats.

In immature rats, Purkinje cells receive synapses from multiple climbing fibers. During development, this multi-innervation regresses and only one climbing fiber innervates each Purkinje cell in the adult. The multi-innervation of immature rats is maintained in the adult if the precursors of the cerebellar granule cells are destroyed by early postnatal X-irradiation. The present study was undertaken to determine the origin of climbing fibers projecting to lobule VI-VII of the cerebellum in X-irradiated granuloprival rats. Olivary neurons were labelled by retrograde transport of wheat germ agglutinin conjugated to horseradish peroxidase, which was injected by iontophoresis in the right vermis of lobule VI-VII. Three-dimensional reconstructions of the inferior olive were made for granuloprival and control rats. No significant variation in the shape and dimension of the olive was observed between the two groups. Labeled cells were found in the middle part of the median accessory olive (MAO). In control rats, stained cells were found only in the contralateral MAO, whereas in the granuloprival rats they were located in both the contralateral and the ipsilateral MAO. Homologous zones were marked in control and granuloprival rats in the middle part of MAO. In granuloprival rats, there was a symmetry in the distribution of the stained cells in the ipsi- and contralateral MAO along the three axes. Therefore, polyinnervation involves homologous regions of both inferior olivary nuclei.

Animals↗
PubMed1991

Autoradiographic characterization of [3H]L-glutamate binding sites in developing mouse cerebellar cortex.

Postnatal changes of [3H]L-glutamate binding sites in mouse cerebellum were studied by in vitro autoradiography. These sites were already present at birth, their density globally increased until postnatal day 25, and at all ages it was higher when Cl- and Ca2+ were present in the incubation buffer. At birth, these binding sites were diffused through the whole cerebellar mass, but became distinctly concentrated in the molecular and the internal granular layers by postnatal day 10. From this age on, binding site sensitivity to ions and glutamate analogues takes a different course in each layer. The external granular layer and the white matter never displayed significant amounts of binding. In the molecular layer the Cl-/Ca2+ effect increased during ontogeny until, in adults, the ion-dependent binding was threefold higher than the ion-independent binding. Quisqualate-sensitive sites accounted for 80% of the total binding sites already at postnatal day 15, while displacement by alpha-amino-3-hydroxy-methyl-4-isoxazolepropionic and ibotenic acids attained the maximum (68%) at postnatal day 60. N-Methyl-D-aspartate displaced glutamate binding (50%) only in the presence of Cl- and Ca2+. Starting from postnatal day 15, binding site density in the molecular layer of lobules VIb and VII of the vermis was lower than in other lobules. In the internal granular layer, the Cl-/Ca2+ effect observed in young animals decreased during development. These transient binding sites were sensitive to quisqualic and ibotenic acid. In adults, the majority of glutamate binding sites were ion-independent and mainly sensitive to D,L-amino-5-phospho-valeric acid and N-methyl-D-aspartate. Throughout development and in both layers, sites displaced by kainate were present at low density and sites displaced by D,L-2-amino-4-phosphonobutyric acid were not detected. The localized postnatal changes of the [3H]L-glutamate binding sites were correlated with the events occurring during growth and maturation of cerebellar structures. The increase of the Cl-/Ca(2+)-dependent binding in the molecular layer is simultaneous with the growth of Purkinje cell dendrites and of parallel fibres and with the formation of the synapses between them. This suggests that these binding sites are localized in these synapses. The changing pattern of sensitivity to different agonists during development might correspond to the maturation of these synapses. The low density of [3H]L-glutamate binding in the molecular layer of lobules VIb and VII probably indicates the presence of specific nerve projections to these areas.(ABSTRACT TRUNCATED AT 400 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed2005

Fast oscillation in the cerebellar cortex of calcium binding protein-deficient mice: a new sensorimotor arrest rhythm.

Fast oscillations (>100 Hz) may serve physiological roles when regulated properly. They may also appear in pathological conditions. In cerebellum, 160 Hz oscillation emerge in mice lacking calbindin and/or calretinin, two proteins devoted to calcium buffering in Purkinje and granule cells, respectively. Here, we review the pharmacological and spatiotemporal properties of this fast cerebellar oscillation and the related Purkinje cell firing behaviour in alert mice. We show that this oscillation is highly synchronized along the parallel fiber beam and reversibly inhibited by gap junctions, GABA(A) and NMDA receptors blockers. Cutaneous stimulation of the whisker region transiently suppressed the oscillation which shows in some aspects similarities with cerebral "resting" rhythmic activities of wakefulness arresting to sensory or motor information such as alpha and mu rhythms. The Purkinje cells of these mutants present an increased simple spike firing rate, rhythmicity and synchronicity, and a decreased complex spike duration and subsequent pause. Both simple and complex spikes may be tightly phase-locked with the oscillation. Contrastingly, on slice recordings, the intrinsic membrane properties of Purkinje cell are similar in wild type mice and in mice lacking calbindin. The role played by this fast cerebellar oscillation in the emergence of ataxia is yet to be solved.

Animals↗
PubMed1984

Alterations in the postnatal development of the cerebellar cortex due to zinc deficiency. III. Impaired dendritic differentiation of basket and stellate cells.

The effects of zinc deficiency and undernutrition on the dendritic differentiation of basket and stellate cells were studied in 21-day-old rats. A morphometric analysis of the dendritic branching of basket and stellate neurons was used that took into account the cell's position in the molecular layer. Zinc deficiency and undernutrition during the suckling period impaired the dendritic differentiation of cerebellar basket and stellate cells. The effects of zinc deficiency were not due totally to the reduced food intake of lactating dams. In the lower 65-75% of the molecular layer of zinc-deficient (ZD) pups, the dendritic field area, the total dendritic length and the number of branches per interneuron were reduced by 45-61%. In the lower 50-60% of the molecular layer, undernutrition reduced the dendritic field area, the total dendritic length and the number of branches per neuron by 32-44%. A comparison of ZD and undernourished (pair-fed) pups indicated that the dendritic field area and total dendritic length of neurons of ZD animals were 43% and 30% smaller in the lower half of the molecular layer. The number of branches per neuron was not significantly different between ZD and undernourished animals. The area of the soma was unaffected by dietary treatment. A delay in the onset of dendritic differentiation and a retarded rate of dendritic growth were considered possible mechanisms for the impaired dendritic differentiation.

Aging↗
PubMed2007

Perisynaptic organization of plasma membrane calcium pumps in cerebellar cortex.

Calcium, a ubiquitous intracellular messenger, regulates numerous intracellular signaling pathways. To permit specificity of signal transduction and prevent unwanted cross-talk between pathways, sites of calcium entry in neurons are localized to specific membrane domains. To test whether Ca(2+) extrusion pumps might exhibit analogous compartmentalization, we used immunohistochemistry to determine the subcellular localization of the two main plasma membrane Ca(2+)-ATPase (PMCA) isoforms in the cortex of the rat cerebellum. We find that both PMCA2 and PMCA3 are targeted to distinct compartments within the plasma membrane. In the molecular layer, both isoforms were at highest levels within synaptic profiles, but PMCA2 was postsynaptic and PMCA3 was presynaptic. Moreover, inside these compartments, both pumps exhibited nonuniform distributions. These data imply that cerebellar neurons possess remarkably effective mechanisms to target and restrict PMCA2 and -3 to specific membrane domains, raising the possibility that calcium pumps contribute to local Ca(2+) signaling.

Animals↗
PubMed1991

Efferent connections of lobule IX of the posterior cerebellar cortex in the rabbit--some functional considerations.

The Purkinje cell projection from the cardiovascular region of sublobule b of the uvula (medial area of zone A) has been investigated using anterograde tracing methods in the rabbit. The importance of the integrity of the identified pathways in mediating the cardiovascular responses from the uvula has been studied in subsequent lesioning experiments. Wheat germ agglutinin-conjugated horseradish peroxidase or tritiated amino acids were microinjected into sublobule IXb. This resulted in anterogradely labelled Purkinje cell axons in both the inferior and superior cerebellar peduncle. In agreement with previous studies in rabbit we also found labelled fibres at the level of the fastigial nucleus and vestibular complex. However, the labelled fibres we observed in the parabrachial nucleus have not been reported in previous studies except in the prosimian primate. Projections from IXb showed terminal-like patterns of label in the ventromedial region of the caudal fastigial nucleus, the dorsal areas of the superior and inferior vestibular nuclei and in the medial and lateral divisions of the parabrachial nucleus. Labelled fibres were also seen coursing in the lateral vestibular nucleus. Lesioning experiments have revealed that the integrity of the superior cerebellar peduncle is essential for the expression of the cardiovascular responses (bradycardia and depressor response) elicited from the uvula in the anaesthetized rabbit. In contrast, the pattern of cardiovascular response evoked in a decerebrate rabbit (tachycardia and pressor response) was abolished when the inferior cerebellar peduncle was lesioned.

Amino Acids↗
PubMed1991

Effects of hypothyroidism on the detyrosylation of alpha-tubulin in the parallel fibers of the developing rat cerebellar cortex.

The immunocytochemical staining of tyrosylated alpha-tubulin using the specific monoclonal antibody YL 1/2 decreases dramatically in the parallel fibers of the rat cerebellum during development. Detyrosylation starts at 14 days in the deeper part of the molecular layer and then spreads over the entire molecular layer within a week. Thyroid deficiency induces a marked delay in alpha-tubulin detyrosylation in the parallel fibers. Detyrosylation begins only at the age of 28 days in hypothyroid animals. Immunobinding assays of detyrosylated and tyrosylated alpha-tubulin concentrations in the cerebellar supernatant of developing rats confirm that thyroid deficiency increases the tyrosylated alpha-tubulin content at 21 and 35 days. Short-term thyroxine treatment (daily from day 8, 10 or 12, to day 14) do not induce the normal pattern of tubulin detyrosylation starting at 14 days, although they do induce parallel fiber lengthening. Daily treatment from birth is required to produce the alpha-tubulin modification found in normal rats. We propose that the microtubule detyrosylation which occurs during axonal maturation is not a prerequisite for axon growth and synaptic differentiation, but may rather be implicated in the stabilization of microtubules in the mature axons.

Aging↗
PubMed2004

Interactions between glutamate transporters and metabotropic glutamate receptors at excitatory synapses in the cerebellar cortex.

Five glutamate transporter genes have been identified; two of these (EAAT3 and EAAT4) are expressed in neurons and are predominantly confined to the membranes of cell bodies and dendrites. At an ultrastructural level, glutamate transporters have been shown to surround excitatory synapses in hippocampus and cerebellum [J. Neurosci. 18 (1998) 3606; J. Comp. Neurol. 418 (2000) 255]. This pattern of localization overlaps the well-described perisynaptic distribution of Group I metabotropic glutamate receptors or mGluRs [Neuron 11 (1993) 771; J. Chem. Neuroanat. 13 (1997) 77]. Both of the principal excitatory synaptic inputs to cerebellar Purkinje neurons, the parallel fiber (PF) and climbing fiber (CF) synapses, express mGluR-dependent forms of synaptic plasticity [Nat. Neurosci. 4 (2001) 467]. Prompted by the colocalization of postsynaptic glutamate transporters and mGluRs, we have examined whether glutamate uptake limits mGluR-mediated signals and mGluR-dependent forms of plasticity at PF and CF synapses in cerebellar slices. We find that, at PF and, surprisingly also at CF synapses, mGluR activation generates a slow synaptic current and triggers intracellular calcium release. At both PF and CF synapses, mGluR responses are strongly limited by glutamate transporters under resting conditions and are facilitated by short trains of stimuli. Nearly every Purkinje neuron expresses an mGluR-mediated synaptic current upon inhibition of glutamate transport. Global applications of glutamate achieved by photolysis of chemically caged glutamate yield similar results and argue that the colocalized transporters can effectively limit glutamate access to the mGluRs even in the face of such a large amount of transmitter. We hypothesize that neuronal glutamate transporters and Group I mGluRs located in the perisynaptic space interact to sense and then regulate the amount of glutamate escaping excitatory synapses. This hypothesis is currently being tested using electrophysiological methods and the introduction of optically tagged glutamate transporter proteins. In the brain, synaptic signals are terminated mainly by neurotransmitter transporters. Families of genes encoding transporters for the major neurotransmitters (dopamine, GABA, glutamate, glycine, norepinephrine and 5-HT) have been identified. Although transporters serve as targets for important classes of therapeutic drugs (e.g. selective serotonin reuptake inhibitors) and drugs of abuse (amphetamine, cocaine), little is known about how they operate at a molecular level or contribute to synaptic transmission.

Amino Acid Transport System X-AG↗
PubMed1985

Neuronal migration independent of glial guidance: light and electron microscopic studies in the cerebellar cortex of neonatal rats.

Migrating cells from the external germinal layer of the newborn rat cerebellum were studied by light and electron microscopy. Each migrating cell possessed a single, broad, leading process oriented perpendicular to the pial surface. These cell processes were sometimes associated with profiles of other granule cells, but were not necessarily associated with the electron-lucent Bergmann fibers present at these early developmental stages. Migrating granule cells could be observed circumventing both blood vessels and the perikarya/processes of other cells present in the developing molecular layer. Thus, during the early stages of cerebellar ontogeny, when the migration pathway through the molecular layer is sparsely populated with cells and processes, the vertical process of a granule cell may seek actively a path of least resistance, utilizing 'contacts' with surrounding objects for avoidance, rather than as guideposts imperative for directing migration. Cellular associations observed at this stage of cerebellar development may thus be more fortuitous than requisite.

Animals↗
PubMed2006

Synaptic organization of the mouse cerebellar cortex in organotypic slice cultures.

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.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1970

Neurogenesis and morphogenesis in the cerebellar cortex.

The cerebellum presents the best site in the central nervous system for defining fundamental problems concerning the origin and differentiation of neurones, and their growth and development. The many recent experimental investigations of these problems are reviewed, and hypotheses based upon them are developed in relation to neurogenesis, morphogenesis, and synaptogenesis.

Animals↗
PubMed1979

A stereological analysis of the neuronal and synaptic content of the frontal and cerebellar cortex of weanling rats undernourished from birth.

The frontal cortex and granular layer of the cerebellum have been examined in 30-day-old rats undernourished from birth. Quantitative stereological procedures at the light microscopical level have been used to estimate the volume proportion and numerical densities of neuronal nuclei. Similar methods at the electron microscopical level were employed to calculate the numerical densities of synapses. Hence, synapse-to-neuron ratios have been calculated in these brain regions. In the frontal cortex, the undernourished group of rats showed a 37% deficit (P less than 0.05) in the synapse-to-neuron ratio. This was due to a combination of an increase in the numberical density of neurons and a decrease in the numerical density of synapses, although, individually, neither of these reached statistical significance at the 5% level. In the granular layer of the cerebellum there was a 31% (P less than 0.01) deficit in the synapse-to-neuron ratio. This was a function of the reduced numerical density of synapses, with no difference in the numerical density of granule cells between groups. For the frontal cortex, the volume proportion of neuronal nuclei was significantly greater in the undernourished group of rats. There were no significant differences between control and undernourished rats in the volume of the 'forebrain' occupied by cortex. The mean diameters of neuronal nuclei and synaptic discs did not differ in any given region between treatment groups. These observations are discussed in context with the previously published results on synapses and neurons in undernourished animals.

Animals↗
PubMed1984

Developmental changes of chick cerebellar cortex revealed by monoclonal antibodies.

Immunohistochemistry studies of the embryonic and newly hatched chick cerebellum were performed with 13 monoclonal antibodies (MAbs) raised against the embryonic chick optic nerve and a MAb which binds to cell nuclei. Neural MAbs differentially stained Purkinje cells, the external granular layer, molecular layer, internal granular layer, climbing fibers, basket cell axons, Bergmann glia and Ramón y Cajal's ansiform fibers. At the different developmental stages each component responded to MAbs differently. For example, staining of Purkinje cells with MAbs 23C10, 82E10 and 94C2 appeared on day 11 of incubation and disappeared sequentially after day 18. These results reveal molecular heterogeneity not only in cerebellar neurons but also at various developmental stages.

Animals↗
PubMed1998

Expression of pituitary adenylate cyclase activating polypeptide (PACAP) in the postnatal and adult rat cerebellar cortex.

In adult rat, immunostaining for pituitary adenylate cyclase activating polypeptide (PACAP) was demonstrated in the soma and dendrites of Purkinje cells and in nerve fibres around granule cells. PACAP in the Purkinje cells was confirmed by the presence of mRNA. The concentration of PACAP-38 was high after birth and declined to adult levels within a few weeks. At birth PACAP-immunoreactive nerve fibres and a few cells were present in the Purkinje cell layer, but already at postnatal day 7 an adult PACAP immunostaining pattern was found. The findings suggest that PACAP could be a neurotransmitter in the adult cerebellum and provide a morphological correlate for the reported in vitro anti-apoptotic PACAP effects on cerebellar granule cells from 1-week-old rats.

Animals↗
PubMed1993

Compartmentation of the cerebellar cortex by protein kinase C delta.

Six isozymes of protein kinase C were analysed in the rat cerebellum using immunohistochemistry. The results revealed a non-uniform distribution of protein kinase C delta among Purkinje, basket, and stellate cells. Serial-section mapping of the delta immunoreactivity revealed that (i) the number and intensity of labeled Purkinje cells increased from rostral to caudal while labeled basket-stellate cells decreased caudally; (ii) the majority of Purkinje cells were labeled in the nodulus, flocculus, and paraflocculus while the anterior lobules were mostly negative; and (iii) labeled Purkinje cells formed distinct parasagittal bands in lobules 6-9 of the paravermis and vermis. The banding of protein kinase C delta within subsets of Purkinje cells suggests units of cerebellar circuitry with specific signaling properties through protein phosphorylation. The visual-vestibular regions of the cerebellum contained the highest amount of the isozyme.

Animals↗
PubMed1975

Studies on ectopic granule cells in the cerebellar cortex. III. An investigation into the restoration of the external granular layer after partial destruction.

In order to strengthen a hypothesis concerning the occurrence of ectopic granule cells, one of the assumptions made was tested systematically. The reaction of the EGL to partial destruction by various single doses by hydroxyurea at various ages was followed. Under all conditions examined, re-population of the EGL takes place--rapidly after lower doses, slowly after high doses of HU. The phenomena observed are discussed with a view on the hypothesis mentioned. Re-population is beneficial, but may itself be a major pathogenetic factor in certain developmental malformations by upsetting the "time-schedule". The results are also of potential interest for an analysis of the regulation of normal cerebellar morphogenesis.

Age Factors↗