Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline

The exopolysaccharide acetan, elaborated by Acetobacter xylinum, has been investigated. The polysaccharide and a heptasaccharide, obtained on enzymic hydrolysis, corresponding to the repeating unit were characterised by sugar and methylation analysis and by NMR spectroscopy and MS. It is concluded that the polysaccharide is composed of repeating units with the following structure. [formula: see text] The polysaccharide further contains approximately two O-acetyl groups per repeating unit, which have not been assigned, but it appears that they are on primary locations.     

Reduced Purkinje cell size in the cerebellar vermis of elderly patients with schizophrenia

OBJECTIVE: The authors' goal was to compare the size and linear density of Purkinje cells in the cerebellar vermis of subjects with and without schizophrenia. METHOD: Blocks of alcohol-fixed cerebellar vermis were dissected at autopsy from the brains of 14 elderly patients with schizophrenia and 13 elderly subjects with no history of neuropsychiatric illness. The blocks of vermis were sectioned and stained with 1% cresyl violet. The linear density and cross-sectional area of Purkinje cells were measured by using computer-assisted image analysis. The subjects with schizophrenia had been assessed with clinical rating scales within 1 year prior to death. RESULTS: The average cross-sectional areas of Purkinje cells of the patients with schizophrenia were significantly smaller (by 8.3%) than those of the subjects without neuropsychiatric illness. No difference in Purkinje cell linear density was observed between the two groups. Significant correlations were seen between Purkinje cell size and scores on the Mini-Mental State, the Brief Psychiatric Rating Scale, and the antipsychotic drug dose. CONCLUSIONS: These data indicate cerebellar involvement in schizophrenia; they are also consistent with reports of reduced neuronal size in other brain regions of patients with schizophrenia. These findings support a model of wide-spread central nervous system abnormality in schizophrenia.     

Moderate alcohol consumption and loss of cerebellar Purkinje cells

OBJECTIVE: To examine the dose-response effect of alcohol consumption on the number of cerebellar Purkinje cells. DESIGN: A prospective necropsy study combined with detailed reports on use of alcohol from a relative or friend. The number of Purkinje cells was counted in the anterior midsagittal section of the cerebellar vermis, the area of which was measured by computer assisted morphometry. SETTING: Department of forensic medicine, University of Helsinki. SUBJECTS: 66 men, aged 35 to 69 years, subjected to medicolegal necropsy because of sudden or violent death. The average all year daily alcohol consumption over the year was 0 to 10 g in 17 men, 11 to 80 g in 24 men, and more than 80 g in 25 men. MAIN OUTCOME MEASURES: Number of Purkinje cells, alcohol consumption. RESULTS: The numbers and density of Purkinje cells in the cross section of vermis showed a consistent but weak decrease with increasing daily alcohol intake but not with age. A wide variation in the cell counts was observed, especially in men drinking more than 80 g, suggesting differences in the susceptibility to effects of alcohol. Compared with men drinking 40 g or less, a long term moderate consumption of an average of 41 to 80 g daily was associated with a significant average loss of 242 (95% confidence interval 45 to 439) Purkinje cells (15.2%) from a mean of 1583 to 1341 cells. In those drinking 81 to 180 g the average loss was 535 (259 to 811) cells (33.4%) to a mean of 1048 cells. The density of cells in the cross section of vermis also fell significantly by 0.9 cell/mm (0.1 to 1.7) when the daily consumption exceeded 40 g and by 1.4 cell/mm (0.3 to 2.5) when the intake was 81 to 180 g. Only three cases (4.5%) in the series showed macroscopical cerebellar atrophy. CONCLUSION: Long term intake of moderate doses of alcohol daily for 20-30 years may damage the cerebellum before the onset of macroscopical atrophy. Despite distinct individual differences an all year average daily alcohol intake of 41-80 g results in a risk of significant loss of Purkinje cells.     

Symptomatic tethering of the cerebellar vermis: case report

A 25-year-old man with symptomatic tethering of the cerebellum is presented. At the age of 8 days, the patient underwent a limited repair of a posterior fossa encephalocele. He was well until the age of 24 when he began to experience paroxysms of extremity weakness, progressive incoordination, and pain at the base of the skull. Imaging demonstrated a connection between the cerebellar vermis and the subcutaneous tissue underlying the site of the previous encephalocele repair. Exploration of the area with the release of a fibrous stalk resulted in the rapid resolution of the patient's symptoms.     

Postsynaptic current mediated by metabotropic glutamate receptors in cerebellar Purkinje cells

In rat cerebellar slices, repetitive parallel fiber stimulation evokes an inward, postsynaptic current in Purkinje cells with a fast component mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors and a slower component mediated by metabotropic glutamate receptors (mGluR). The mGluR-mediated excitatory postsynaptic current (mGluR-EPSC) is evoked selectively by parallel fiber stimulation; climbing fiber stimulation is ineffective. The mGluR-EPSC is elicited most effectively with increasing frequencies of parallel fiber stimulation, from a threshold of 10 Hz to a maximum response at approximately 100 Hz. The amplitude of the mGluR-EPSC is a linear function of the number of stimulus pulses without any apparent saturation, even with >10 pulses. Thus mGluRs at the parallel fiber-Purkinje cell synapse can function as linear detectors of the number of spikes in a burst of activity in parallel fibers. The mGluR-EPSC is present from postnatal day 15 and persists into adulthood. It is inhibited by the generic mGluR antagonist (RS)-a-methyl-4-carboxyphenylglycine and by the group I mGluR antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid at a concentration selective for mGluR1. Although the intracellular transduction pathway involves a G protein, the putative mediators of mGluR1 (phospholipase C and protein kinase C) are not directly involved, indicating that the mGluR-EPSC studied here is mediated by a different and still unidentified second-messenger pathway. Heparin, a nonselective antagonist of inositol-trisphosphate (IP3) receptors, has no significant effect on the mGluR-EPSC, suggesting that also IP3 might be not required for the response. Buffering intracellular Ca2+ with a high concentration of bis-(o-aminophenoxy)-N,N,N', N'-tetraacetic acid partially inhibits the mGluR-EPSC, indicating that Ca2+ is not directly responsible for the response but that resting Ca2+ levels exert a tonic potentiating effect on the mGluR-EPSC.     

Effects of chronic ibogaine treatment on cerebellar Purkinje cells in the rat

The present investigation assessed the chronic toxicity of ibogaine on cerebellar Purkinje cells in male Fischer 344 rats. A behaviorally active dose of ibogaine (10 mg/kg, i.p.) was administered to a group of six subjects every other day for 60 days while the control group received an equivalent volume of saline (1 ml/kg). Estimates of Purkinje cell number were determined using the optical dissector/fractionator technique. No significant differences in Purkinje cell number were observed between the ibogaine (243764[+/-32766]) and control groups (230813[+/-16670]).     

Discharge properties of Purkinje cells in the oculomotor vermis during visually guided saccades in the macaque monkey

1. We previously described discharge properties of cerebellar output cells in the fastigial nucleus during ipsilateral and contralateral saccades. Fastigial cells exhibited unique responses depending on the direction of saccades and were involved in execution of accurate targeting saccades. Purkinje cells in the oculomotor vermis (lobules VIc and VII) are thought to modulate these discharges of fastigial cells. In this study we reexamine discharge properties of Purkinje cells on the basis of this hypothesis. 2. Initially we physiologically identified the right and left sides of the oculomotor vermis. Saccade-related discharges of 79 Purkinje cells were recorded from both sides of the vermis during visually guided saccades toward the sides ipsilateral and contralateral to the recording side in two trained macaque monkeys. To clarify the correlation of Purkinje cell discharge with burst activities in the fastigial nucleus during saccadic eye movements, we analyzed our data by employing methods used in the study of fastigial neurons. 3. Among the 79 cells, 56 (71%) showed burst discharges during saccades (saccadic burst cells). Of the 56 cells, 29 exhibited a peak of burst discharges in both the contralateral and ipsilateral directions (bidirectional cells). The remaining 27 saccadic burst cells showed a peak of burst discharges during either contralateral or ipsilateral saccades (unidirectional cells). Among the 79 cells, 14 (18%) exhibited a pause of discharges during contralateral saccades (pause cells). Among the 79 cells, 9 (11%) showed burst discharge during contralateral saccades followed by tonic discharge that was correlated with eye position (burst tonic cells). 4. The timing of bursts in bidirectional cells with respect to saccade onset was dependent on the direction of saccade. During ipsilateral saccades, Purkinje cells exhibited a long lead burst that built up gradually, peaked near the onset of the saccade, and terminated sharply near midsaccade. The mean lead time relative to saccade onset was 29.3 +/- 24.5 (SD) ms. During contralateral saccades, Purkinje cells exhibited a short lead/late burst that built up sharply, peaked near midsaccade, and terminated gradually after the end of the saccade. The mean lead time relative to saccade onset was 10.7 +/- 20.8 ms. The burst onset time during contralateral saccades and the burst offset time during ipsilateral saccades preceded the saccade offset time by about the same interval regardless of the saccade amplitude. 5. In pause cells the pause preceded saccade onset by 17.5 +/- 10.6 ms. The duration of the pause was not correlated with the duration of saccades. There was little trial-to-trial variability in the onset time of the pause with respect to the onset of saccades, whereas there was large trial-to-trial variability in the offset time of the pause with respect to the offset of saccades. In addition, the mean onset time of the pause for each cell had a relatively narrow distribution. 6. The burst lead time of burst tonic cells relative to saccade onset was 9.5 +/- 3.9 ms. The tonic discharge rate of burst tonic cells was a nonlinear function of eye position. The regression of each cell was fit to two lines. The regression coefficient ranged from 0.95 to 0.99 (mean = 0.97). 7. Axons of Purkinje cells in the oculomotor vermis are thought to project exclusively to saccadic burst cells in the fastigial oculomotor region (FOR), which is located in the caudal portion of the fastigial nucleus. Our previous studies indicated that FOR cells provide temporal signals for controlling targeting saccades. The present results suggest that Purkinje cells in the oculomotor vermis modify the temporal signals of FOR cells for saccades in different directions and amplitudes. The modification of FOR cell activity by Purkinje cells is thought to be essential for the function of the cerebellum in the control of saccadic eye movements.     

The growth of the dendritic trees of Purkinje cells in irradiated agranular cerebellar cortex

The heads of noenatal Wistar rats were irradiated with 200 rads daily from birth to the 10th day post-partum. Ten litters each containing 5 animals were killed at 30 days post-partum and their brains treated by the Golgi-Cox technique. The dendritic trees of 24 Purkinje cells were analysed using the quantitative technique of network analysis, and comparisons made between parameters obtained from 20 normal Purkinje cells. All dendritic trees in agranular irradiated cortex were markedly reduced in size (as indicated by total dendritic length and total number of segments) although mean path lengths were normal. Segment lengths were normal over proximal branches, but uniformly increased over distal branches. Abnormal appendages, called 'giant spines' were observed on many dendrites. They were often some 10 mum in length and their presence effectively reduced segment lengths, increased the frequency of trichotomy and deviated growth from the normal random terminal pattern so that long collateral branching topologies were formed. Nevertheless, trichotomy was uniformly reduced in those trees without 'giant spines' and the distribution of branching patterns suggested that growth had proceeded by random terminal dichotomy. These results demonstrate that the development of dendritic trees is retarded in the agranular irradiated cerebellum, where synaptogenesis is very greatly reduced below normal. The quantitative changes in segment lengths, size of trees, and trichotomy accord with those predicted by the filopodial synaptogenic hypothesis of dendritic growth formulated by Vaughn et al. 99, whilst the results of the topological analysis suggest that branching is established by a degree of non-random interaction between growing dendrites and their substrate. 'Claw-like' dendritic complexes within some Purkinje cell trees may have been induced by aberrent fibre bundles of few surviving granule cells.     

IP3-activated calcium-permeable channels in the inside-out patches of cultured cerebellar Purkinje cells

Inositol-1,4,5-trisphosphate (IP3)-activated calcium-permeable channels were recorded from inside-out patches of cultured cerebellar Purkinje cells. When 2-5 microM of IP3 was applied to the internal surface of the inside-out patches, inward Ba2+ currents were activated within 10 sec following the application in 11 out of 24 patches. In the presence of heparin (100 micrograms/ml), activation of Ba2+ currents by IP3 was inhibited. Unitary currents with different amplitudes and kinetics were observed; small and large unitary currents, and rapid fluctuations with various amplitudes. The small unitary currents (single channel conductance; 5.6 pS) were most frequent. Addition of inositol 1,3,4-trisphosphate (2-5 microM) slightly activated Ba2+ currents in 2 out of 10 patches, but the amount of the increment was much smaller than that produced by IP3. These results suggest a possibility that IP3 directly activates Ca(2+)-permeable channels in the plasma membrane of cerebellar Purkinje cells.     

An immunohistochemical study of Purkinje cells in a case of hereditary cerebellar cortical atrophy

We report an immunohistochemical study of Purkinje cells located in the molecular layer (ectopic Purkinje cells) and in the Purkinje cell layer (orthotopic Purkinje cells) of a patient who died young and had been diagnosed with hereditary cerebellar cortical atrophy from both clinical and neuropathological findings. All the ectopic and orthotopic Purkinje cells were immunoreactive with an anti-calbindin-D antibody, confirming that these stained cells were Purkinje cells. The perikarya of some ectopic and orthotopic Purkinje cells were stained by an antibody to phosphorylated neurofilament. In contrast, Purkinje cells of three normal controls did not react with this antibody. This finding of an abnormal accumulation of phosphorylated neurofilaments in the perikarya may be due to abnormal phosphorylation. Moreover, the regions around the cell bodies of some ectopic and orthotopic Purkinje cells were intensely immunoreactive with an antibody to synaptophysin, which suggests an abnormal increase in presynaptic terminals. It is suggested that ectopia of Purkinje cells, accumulation of phosphorylated neurofilament in the perikarya and an abnormal increase in presynaptic terminals around the soma of the Purkinje cells may be relevant to the pathophysiology of Purkinje cell degeneration in this case. In addition, the relationship between phosphorylated neurofilament and synaptophysin reactivity is discussed.     

Altered axon terminals containing concentric lamellar bodies of cerebellar Purkinje cells in Mongolian gerbil

Altered axon terminals containing concentric lamellar bodies were observed in cerebellar and vestibular nuclei of the Mongolian gerbil. The terminals increased in number from 30 days of age onward, and reached about tenfold at 360 days. The numbers were the same in two gerbil strains with different susceptibility to spontaneous motor seizures by various stimuli, but about threefold those in Slc:Wistar rat.     

Differential expression of glutamate decarboxylase messenger RNA in cerebellar Purkinje cells and deep cerebellar nuclei of the genetically dystonic rat

The genetically dystonic rat exhibits a motor syndrome that closely resembles the human disease, generalized idiopathic dystonia. Although in humans dystonia is often the result of pathology in the basal ganglia, previous studies have revealed electrophysiological abnormalities and alterations in glutamate decarboxylase, the synthetic enzyme for GABA, in the cerebellum of dystonic rats. In this study, we further characterized the alterations in cerebellar GABAergic transmission in these mutants by examining the expression of the messenger RNA encoding glutamate decarboxylase (67000 mol. wt) with in situ hybridization histochemistry at the single cell level in Purkinje cells and neurons of the deep cerebellar nuclei. Glutamate decarboxylase (67000 mol. wt) messenger RNA levels were increased in the Purkinje cells and decreased in the deep cerebellar nuclei of dystonic rats compared to control littermates, suggesting opposite changes in GABAergic transmission in Purkinje cells and in their target neurons in the deep cerebellar nuclei. In contrast, levels of glutamate decarboxylase (67000 mol. wt) messenger RNA in the pallidum, and of enkephalin messenger RNA in the striatum, were unaffected in dystonic rats. The data indicate that both the Purkinje cells and GABAergic neurons of the deep cerebellar nuclei are the site of significant functional abnormality in the dystonic rat.     

Responses to eccentric rotation in two space-bound subjects

Two subjects were rotated eccentrically in the manner described previously. In contrast to a normal control group, settings of a luminous line to the subjective vertical were almost unrelated to the gravitoinertial vector before, and totally so shortly after, space flight. Only 3 days postflight did a clear relation to the gravitoinertial vector re-establish itself in the one subject who actually flew. The correspondence became normal 5 days after the flight. Since there were no clinical abnormalities evident in the subjects, it is suggested that both subjects suppressed their vestibular information, presumably as an effect of vestibular deconditioning training before the flight. In addition, as a consequence of the flight experience one subject continued to ignore it several days after the flight.     

Lesions of the cerebellar vermis and cerebellar hemispheres: Effects on heart rate conditioning in rats.

The effects of lesions of the cerebellum on the acquisition of heart rate (HR) conditioned responses (CRs) were examined in rats. Large lesions of the cerebellar vermis severely attenuated the acquisition of differentially conditioned bradycardic responses in restrained rats without affecting unconditioned HR responses to the tone conditioned stimuli (CSs) or the shock unconditioned stimulus/stimuli (UCS). In Exp 2, Ss were trained unrestrained, and under these conditions the CR was tachycardia in control Ss. Lesions of the vermis again severely attenuated acquisition of this CR without affecting unconditioned response (UCR) to the CSs or UCS. Bilateral lesions of the cerebellar hemispheres did not affect HR conditioning in either test procedure. The vermis of the cerebellum is an essential component of an HR conditioning circuit in the rat. The cerebellar hemispheres, which are involved in some discrete somatomotor CRs, have no essential functional contribution to HR conditioning. Results are discussed in relation to contributions from a forebrain system involved in HR conditioning and in relation to lateral cerebellar contributions to discrete somatomotor CRs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The differences in growth of cerebellar vermis between appropriate-for-gestational-age and small-for-gestational-age newborns

Positive and negative symptoms are measurable characteristics that may represent core features of schizophrenia and offer a quantitative approach for studying the genetics of schizophrenia and related disorders. The Positive and Negative Syndrome Scale (PANSS) was used to assess 72 members of five families segregating schizophrenia. The study confirmed high internal reliability of PANSS scales in this sample with diverse lifetime diagnoses. Gender but not alcoholism affected scores. Schizophrenia/schizoaffective and schizophrenia spectrum disorder groups had higher mean scores for the positive and negative scales than other lifetime diagnostic groups, consistent with genetic transmission of these symptoms. Positive and negative symptom patterns did not subtype families. The results support the validity of positive and negative symptom measures as independent dimensions in familial schizophrenia.     

Effects of lesions to the cerebellar vermis and hemispheres on timing and counting in rats.

The effects of lesions to the cerebellum on numerical and temporal discrimination were examined in rats using a psychophysical choice procedure. Lesions to the cerebellar hemispheres but not the cerebellar vermis produced performance deficits in a numerical discrimination task (2–8 events) and a milliseconds temporal discrimination task (0.2–0.8 s). However, temporal discriminations in the seconds range (2–8 s) were unaffected by either type of lesion. Using W. H. Meck and R. M. Church's (1983) mode-control model of timing and counting, these findings suggest that damage to the cerebellar hemispheres influences a source of constant variability (e.g., switch processes) because constant variability is a prominent source of error during both milliseconds timing and counting but is masked by other sources of variability when timing longer durations (>2 s). (PsycINFO Database Record (c) 2010 APA, all rights reserved)