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B Ghetti

Publications and source records attributed to B Ghetti.

At least 163 records · Page 9Linked to original sources
PubMed1988

Autoradiographic localization of insulin-like growth factor II receptors in cerebellar cortex of weaver and Purkinje cell degeneration mutant mice.

Autoradiography was used to visualize insulin-like growth factor II (IGF-II) receptors in the cerebellar cortex of weaver and Purkinje cell degeneration (pcd) mice. These mutants were selected for their respective absence of granule or Purkinje cells. Histological preparations confirmed a severe loss of granule cells in the cerebella of weaver mutants and an absence of Purkinje cells in those of pcd mutants. Autoradiographs showed specific IGF-II binding to the granule cell layer of the cerebellar cortex in control mice, and in pcd mutants. No specific [125I]human IGF-II binding was observed in the cerebellar cortex of weaver mutants. These studies suggest that specific IGF-II receptor sites are located on the granule cells of the cerebellum.

Animals↗
PubMed1988

Serotonin concentration and turnover in cerebellum and other brain regions of pcd mutant mice.

The Purkinje cell degeneration (pcd) mutant mouse is characterized by a loss of Purkinje cells in the cerebellum. Loss of granule cells occurs and is severe in pcd mutants after 9 months of age. Since Purkinje cells and granule cells represent two groups of target cells for serotonin neurons projecting from raphe nuclei and other brain areas, the content and turnover of serotonin in the cerebellum were determined in pcd mice aged 3-15 months. The content of serotonin was not decreased in pcd mouse cerebellum but tended to be slightly increased after 7 months. The ratio of 5-hydroxyindoleacetic acid (5-HIAA) to serotonin was significantly decreased in cerebellum at 7-15 months but not at 3 or 6 months. The decrease in this ratio is indicative of decreased serotonin turnover. Similar changes were not seen in brainstem or hypothalamus in mice up to 14 months old, but slight decreases were observed at 15 months. Another index of turnover, the accumulation of 5-HIAA after administration of probenecid to block its efflux from brain, was decreased by 46% in 7-month-old pcd mice in the cerebellum but not in the brainstem or hypothalamus. The decrease in serotonin turnover in pcd mouse cerebellum occurs subsequent to and perhaps due to the loss of the target Purkinje and granule cells.

Aging↗
PubMed1988

Layer-specific innervation of the dopamine-deficient frontal cortex in weaver mutant mice by grafted mesencephalic dopaminergic neurones.

The dopamine innervation of the frontal cortex originates in the A9 and A10 mesencephalic dopamine cell groups. In weaver mutant mice, there is a 77% frontocortical dopamine deficiency associated with losses of dopamine neurones in areas A9 and A10. The dopamine-depleted cortical areas of weaver mutant mice are receptive to reinnervation by afferent fibres originating in dopamine-containing mesencephalic grafts from normal donor embryos. In the anteromedial frontal lobe, reinnervation by tyrosine hydroxylase immunoreactive fibres is largely confined to the basal cortical layers whereas in the anterior cingulate cortex, tyrosine hydroxylase immunoreactive fibres also occupy superficial layers, including the molecular layer. Normally, the dopaminergic innervation of the anteromedial frontal lobe is distributed among the basal cortical layers (IV-VI), and the dopaminergic innervation of the cingulate cortex occupies both basal and superficial cortical layers. The pattern of innervation following transplantation indicates that, in repopulating dopamine-deficient cortical areas of recipient weaver mutants, graft-derived dopamine fibres show a preference for those layers which are normally invested by dopamine afferents.

Animals↗
PubMed1988

Mesencephalic dopamine cell deficit involves areas A8, A9 and A10 in weaver mutant mice.

The mesencephalic dopamine (DA) cell system was examined in mice homozygous and heterozygous for the weaver (wv) gene and in wild-type controls to estimate the extent of cell losses associated with the genetically determined central DA deficiency observed in weaver homozygotes. Animals of the three genotypes (+/+, wv/+, wv/wv) were studied at postnatal day (P)20 and P90. Serial coronal sections were obtained through the brainstem. Half of the sections were immunolabeled with antiserum to tyrosine hydroxylase (TH). Cell counts were obtained in areas A8 (retrorubral nucleus, RRN), A9 (substantia nigra, SN), and A10 (ventral tegmental area, VTA). The counts were analyzed with repeated measures analysis of variance followed by individual comparisons among group means. In A8, weaver homozygotes did not differ significantly from wild-type controls at P20, whereas there was a significant difference of 56% at P90. In A9, weaver homozygotes differed significantly from wild-type mice by 42% at P20 and by 69% at P90. The decrease in cell number between P20 and P90 in weaver homozygotes was 54%. In A10, weaver homozygotes did not differ significantly from wild-type controls at P20, whereas there was a significant difference of 26% at P90. Cell numbers in all three areas of heterozygotes did not differ significantly from wild-type control values at either age point. These findings demonstrate that by three months of age homozygous weaver mutants exhibit nerve cell losses in all three areas of the mesencephalic DA cell system. Such losses account for the DA deficiency seen in striatal, limbic and cortical projection fields.

Age Factors↗
PubMed1988

Progressive supranuclear palsy with hypertrophy of the olives. An immunocytochemical study of the cytoskeleton of argyrophilic neurons.

In a patient with progressive supranuclear palsy (PSP) and hypertrophy of the olives, neurons with different forms of argyrophilic degeneration were detected by means of Bodian's silver staining method, i.e., neurofibrillary tangle-bearing neurons in the basal ganglia and brain stem, ballooned argyrophilic neurons in the brain stem, and hypertrophied neurons in the olives. In these cells, the cytoskeleton was investigated to ascertain whether neurons with different cytoskeletal changes contained phosphorylated neurofilaments (P-Nf) in the perikaryon. This study, carried out using two monoclonal antibodies that recognize phosphorylated epitopes of the neurofilament high molecular weight subunits, showed that hypertrophied olivary neurons, most ballooned neurons and a small aliquot of tangle-bearing neurons were labelled. The immunostaining of hypertrophied and ballooned neurons was localized in the whole perikaryon and dendrites, whereas that of tangle-bearing neurons was confined to the tangle. These findings were reproduced in five additional patients (one with hypertrophy of the olives, four with PSP) and demonstrated that, in PSP, the mechanism responsible for tangle formation does not affect the ability of neurons to accumulate P-Nf. This fact suggested that perikaryonal P-Nf accumulation is likely to be part of the cell reaction to abnormal conditions affecting the neuronal cytoskeleton.

Brain↗
PubMed1988

Changes in the content of glutamate and GABA in the cerebellar vermis and hemispheres of the Purkinje cell degeneration (pcd) mutant.

The contents of glutamate and GABA, as well as aspartate, glycine, and alanine, were examined in the cerebellar vermis and hemispheres of normal and Purkinje cell degeneration (pcd) mutant mice at 6, 9, and 12 months of age. Relative to normal values, the content of glutamate was approximately 50% lower in the vermis for the 3 age groups. In the hemispheres, the content of glutamate was also lower than control values and showed a progressive loss from 30 to 47% with age. On the other hand, in the case of GABA in the vermis, the level was 39% lower in the pcd mutant at 6 months of age but no different from control values at 12 months. However, relative to data for normal mice, the content of GABA in the hemispheres was consistently lower (20%) for all age groups. The level of aspartate was approximately 60% lower in the cerebellar vermis and 45 to 55% lower in the hemispheres of the mutant with respect to control data for all three age groups. Likewise, alanine showed a reduced content in the hemispheres (36-46%) and vermis (24%) in the mutant relative to normal values at 6, 9, and 12 months of age. On the other hand, the level of glycine was 43-64% higher in the vermis and 77-100% greater in the hemispheres of the mutant than in the control group. The higher values for glycine were observed at the two oldest ages. In conclusions, the data are consistent with the idea that glutamate and GABA are present in high concentrations in granule and Purkinje cells, respectively, and provide additional support for a transmitter function for both amino acids in the cerebellum.

Alanine↗
PubMed1988

Synaptic connectivity of tyrosine hydroxylase immunoreactive nerve terminals in the striatum of normal, heterozygous and homozygous weaver mutant mice.

Striatal dopamine deficiency in weaver mutant mice is associated with loss of mesencephalic dopamine neurons. The maximum dopamine concentration in the striatum of weaver mutants is found on postnatal day 20, when it represents 50% of the control value. By day 180, it declines to 25% of the control value. Correspondingly, the number of nigral dopamine neurons is 58% of the normal number on day 20 and becomes 31% of the normal value by day 90. The aim of the present study was to examine whether dopamine axon terminals in the weaver striatum establish synaptic connections with postsynaptic neurons at the time when striatal dopamine concentration is at its peak value (i.e. on postnatal day 20), and if so, to compare the profile of synaptic connectivity of dopamine axon terminals found in the striatum of normal mice with that of heterozygous and homozygous weaver mutants. To that end, 20-day-old weaver homozygotes, along with age-matched weaver heterozygotes and wild-type mice were studied by electron microscopy after immunocytochemical labelling for tyrosine hydroxylase. A single micrograph of each of 1543 dopamine axon terminals was examined in total in the three genotypes; quantitative analyses of the relations of tyrosine hydroxylase immunoreactive nerve terminals were carried out in the dorsolateral striatum, which receives the dopamine projection from the substantia nigra proper. In all three genotypes, junctional contacts formed by tyrosine hydroxylase immunoreactive nerve terminals in the striatum were predominantly of the symmetrical type. In wild-type and heterozygous mice, the majority of contacts (92% and 91% respectively) were formed with dendrites and spines. In weaver mutant mice, the majority of contacts (87%) were also with dendrites and spines, but the proportion of axosomatic contacts was double that found in normal animals. The proportions of contacts that displayed junctional membrane specializations in single sections were 27% in wild-type mice, 29% in weaver heterozygotes, and 17% in homozygous weaver mutants. Taking into consideration that the plane of the section might not always have included the synaptic specialization, a stereological formula was applied. It was estimated that 85-89% of the contacts may be truly junctional in the striatum of normal and heterozygous mice, whereas only 53% may be junctional in the striatum of weaver homozygotes. The reduced incidence of junctional synapses in weaver homozygotes may suggest either inadequate synaptogenesis, or an early loss of synapses after their formation, or both.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Reinstatement of synaptic connectivity in the striatum of weaver mutant mice following transplantation of ventral mesencephalic anlagen.

Ventral mesencephalic anlagen survive following grafting to the striatum of weaver mutant mice and reinnervate the dopamine-depleted basal ganglia of the recipients. The aim of the present study was to examine the pattern of connectivity established by graft-deriving dopamine afferents in the host striatum. Grafts were obtained from normal embryos at a gestational age of 14-15 days and implanted into a surgical cavity overlying the dorsal striatum of adult weaver recipients. Tissue was processed for electron microscopic immunocytochemistry using a primary antiserum against tyrosine hydroxylase. At the time of examination, recipient weaver mutants were 8.5 months old and the grafts had survived for 4.5 months. Grafts were found to contain an estimated 100-1000 tyrosine hydroxylase immunoreactive neurons. Tyrosine hydroxylase immunoreactive fibres, displaying characteristic varicosities, innervated the dorsal striatum to a depth of 1000 micron. In the non-grafted striatum, 8% of the contacts of tyrosine hydroxylase immunoreactive nerve terminals were junctional. That proportion contrasted with the corresponding value of normal animals, which is 27%. In the grafted striatum, 29% of the contacts were junctional. That percentage approximated the value found in normal animals. By applying a stereological correction, it can be estimated from those numbers that the true proportion of junctional contacts in the non-grafted striatum of 8.5-month-old mutants may be 26%, whereas that in the grafted side may be 91%, which is close to the normal situation. The majority of contacts in the reinnervated striatum (84%) were made with dendrites and spines. However, the proportion of total axosomatic contacts in the reinnervated striatum was twice as high as that found in the striatum of normal animals, and the proportion of junctional synapses was three times higher than that found normally. We conclude that: (1) in spite of a genetically determined degenerative process, the dorsal neostriatum of weaver mutant mice is receptive to synaptic investment by dopamine afferents originating in normal donor tissue. (2) In repopulating the denervated weaver striatum, graft-deriving dopamine afferents display a connectional selectivity, i.e. they establish synaptic relations preferentially with those cellular domains that are normally innervated by dopamine nerve terminals. In this context, it is possible that dopamine fibres originating in the grafts invest postsynaptic sites that had either been vacated from the intrinsic dopamine input or had never received such an input. (3) The striatal connectivity following transplantation may retain features of immaturity as suggested by t

Animals↗
PubMed1987

Functional innervation of the striatum by ventral mesencephalic grafts in mice with inherited nigrostriatal dopamine deficiency.

Weaver mutant mice are characterized by a decrease in striatal dopamine (DA), which is associated with a progressive loss of DA neurones in the substantia nigra. This mutant thus provides the opportunity to examine the functional effects of DA neurones grafted to the striatum in a genetic model of parkinsonism. Ventral mesencephalic tissue from normal foetuses was placed on the surface of the right dorsal striatum of adult weaver mutants. After grafting, animals were tested for methamphetamine-induced circling behaviour. Mutants with DA containing grafts displayed a significant circling bias toward the left, non-grafted side. Mutants without grafts did not display any rotational bias to either side. These results demonstrate that grafted DA containing neurones establish a functional innervation of the weaver striatum and suggest that grafting of neural tissue is a viable approach in restoring function in genetic degenerative disorders of the nigrostriatal system.

Animals↗
PubMed1987

Dopamine D2 receptors increase in the dorsolateral striatum of weaver mutant mice.

Dopamine D2 receptors were studied in homozygous weaver mutant mice (wv/wv), heterozygous littermates (wv/+), and normal mice (+/+). Specific [3H]spiperone binding was significantly higher in the dorsolateral part of the striatum in the weaver mutant mice (wv/wv) than in normal mice (+/+). No significant differences among the 3 genotypes were found in other parts of the striatum or in the nucleus accumbens.

Animals↗
PubMed1987

Nerve cell atrophy and loss in the inferior olivary complex of "Purkinje cell degeneration" mutant mice.

The genetically determined loss of cerebellar Purkinje cells (PCs) in "Purkinje cell degeneration" (pcd) mutant mice deprives inferior olivary (IO) neurons of their major postsynaptic target. The degeneration of PCs starts on postnatal day (P) 17 and loss of these neurons is virtually complete by P45. We examined the inferior olivary complex (IOC) of normal and pcd mutant mice by quantitative light microscopy to determine whether the degeneration of PCs is associated with atrophy and loss of their presynaptic neurons in the IOC. The number of IO neurons in 17-day-old mutants did not differ significantly from controls (P greater than .1). IO neurons in 23-day-old mutants were 23% (95% confidence limits: 12-34%) fewer than in age-matched controls, and in 300-day-old mutants they were 48% (95% confidence limits: 37-58%) fewer than in their controls (P less than .001 in both cases). The decline of the number of IO neurons in pcd mice between days 17 and 300 was 49% (P less than .0001; 95% confidence limits: 38-57%). The medial accessory olive (MAO) appeared less affected than the principal (PO) and the dorsal accessory olive (DAO). The mean neuronal diameter in control mice was 11.6 micron at 23 days and 10.8 micron at 300 days of age. The respective values in pcd mutants were 11.5 micron and 8.7 micron. Diameters in old mutants were significantly smaller than those in both age-matched controls and young mutants (P less than .001). These findings suggest that in the mature olivocerebellar system the stability of IO neurons depends on the state of their postsynaptic PCs.

Animals↗
PubMed1987

Selective loss of monoaminergic neurons in weaver mutant mice--an immunocytochemical study.

Tyrosine hydroxylase (TH) immunocytochemistry and quantitative light microscopic analysis of neurons in the substantia nigra pars compacta, the ventral tegmental area, and the locus coeruleus of weaver mutant mice at 12 and 15 weeks of age and unaffected controls revealed a decrease in the number of TH-positive neurons in the substantia nigra of weaver mice, but no change in cell numbers in the ventral tegmental area and locus coeruleus. Furthermore, the 15-week-old mutants showed a significant cell loss in the substantia nigra pars compacta compared with the 12-week-old group. Thus, the weaver mutant may provide a good model for studying the mechanisms of selective dopaminergic cell loss.

Animals↗
PubMed1987

Anterograde transsynaptic degeneration in the deep cerebellar nuclei of Purkinje cell degeneration (pcd) mutant mice.

The genetically-determined loss of Purkinje cells (PCs) in 'Purkinje cell degeneration' (pcd) mutant mice results in the loss of presynaptic afferents to the deep cerebellar nuclei (DCN). This deafferentation takes place between postnatal day (P)17 and P45, i.e. after the maturation of cerebellar circuitry. We examined the DCN of normal and pcd mutant mice by quantitative light microscopic methods to determine whether neuronal atrophy or loss in the DCN take place during and after the loss of their input from the PCs. Neuronal diameters in control mice were 16.4 +/- 0.72 microns (mean +/- S.D.) at P23 and 15.6 +/- 0.64 microns at P300. The respective values in pcd mutant mice were 15.7 +/- 0.58 microns and 13.5 +/- 0.24 microns. Diameters in 300-day-old mutants were significantly smaller than those in both age-matched controls and 23-day-old mutants (P less than 0.001). Neuronal populations in the DCN of control mice were 10,167 +/- 949 at P23 and 10,429 +/- 728 at P300. The respective values in mutants were 9,436 +/- 1,366 and 7,424 +/- 1,324. There was a significant difference of 29% [95% confidence limits: 9-45%] between 300-day-old mutants and age-matched controls (P less than 0.01), and a significant loss of 21% [95% confidence limits: 4-36%] in 300-day-old mutants with respect to 23-day-old mutants (P less than 0.05). The total volume of the DCN was 22% less in 300-day-old mutants in relation to 23-day-old mutants (P less than 0.05). These findings support the idea that the stability of DCN neurons in the mature cerebellum depends in part on the synaptic input from PCs.

Animals↗
PubMed1987

Transplantation of cerebellar anlagen to hosts with genetic cerebellocortical atrophy.

Embryonic cerebellar grafts from genetically normal donors were implanted into the cerebellomedullary cistern of adult 'Purkinje cell degeneration' (pcd) and weaver mutant mice, which are respectively characterized by the selective loss of Purkinje and granule cells. Grafts placed into both mutant recipients exhibited a layered cellular organization reminiscent of the normal cerebellar cortex. Molecular, Purkinje, and granule cell layers were identifiable. Grafted Purkinje cells displayed characteristic cytological features, such as hypolemmal cisterns in association with mitochondria in the perikaryon, and lamellar structures in their axons. The cytological features of granule cell somata in the grafts appeared similar to those of mature granule cells. Electron microscopic examination of the molecular layer of the grafts revealed the presence of parallel fibers, which were not oriented in a parallel fashion; axon terminals of such fibers were often presynaptic to dendritic spines. The number of parallel fibers was markedly reduced in grafts implanted into both mutants compared to the normal cerebellar cortex; however, this phenomenon is commonly seen in cerebellum in tissue culture and in cerebellar transplants into normal hosts. It is concluded, therefore, that the environment of the mutant hosts does not affect the survival of Purkinje or granule cells and that transplantation of solid cerebellar grafts in the neurological mutants studied does not seem to pose any apparent limitations beyond those inherent to the process of cerebellar growth and differentiation outside its normal environment.

Animals↗
PubMed1987

Aluminum-induced decreases in choline acetyltransferase, tyrosine hydroxylase, and glutamate decarboxylase in selected regions of rabbit brain.

The neuropathological and neurochemical effects of intracisternally administered aluminum-powder suspensions were studied in adult rabbits. The right half of each brain was fixed for neuropathological examination, and neurotransmitter-synthesizing enzyme activities were measured in homogenates of structures dissected from the left half of each brain. The neuropathological changes associated with aluminum-induced encephalomyelopathy, including neurofibrillary degeneration, were observed in several regions of the central nervous system of the aluminum-treated rabbits. The striatum was consistently free of changes. Decreases in choline acetyltransferase and tyrosine hydroxylase activities of more than 30% were observed in the striatum of animals within 14-21 d and at longer times after aluminum injection. The decrease in striatal choline acetyltransferase activity appears to be unrelated to pathological changes in the striatal cholinergic neurons. The decrease in tyrosine hydroxylase activity in the striatum may be unrelated to neuropathological changes in dopaminergic cell bodies in the midbrain. Significant decreases in glutamate decarboxylase activity in the cerebellum may be related to cell losses in this region, whereas choline acetyltransferase activity deficits in the whole hippocampus remain unexplained.

Aluminum↗
PubMed1986

Noradrenergic innervation of the cerebellar cortex in normal and in Purkinje cell degeneration mutant mice: evidence for long term survival following loss of the two major cerebellar cortical neuronal populations.

Purkinje cell degeneration mutant mice were examined during the course of Purkinje cell death (26 and 35 days old) and at 3, 5, 9 and 12 months of age. Glyoxylic acid fluorescence histochemistry for catecholamines was used to investigate possible alterations or reorganization of the noradrenergic fibers from the coeruleo-cerebellar system in response to the degeneration of two major cell types in the cerebellar cortex, of which one, the Purkinje cell, is reported to be the major target neuron. In control mice, noradrenergic fibers traveled in linear and tortuous profiles through the granule cell layer, formed pericellular arrays alongside Purkinje cell somata, and branched profusely into both radially oriented and longitudinally oriented chains. The density of noradrenergic varicosities diminished in the molecular layer, there was with age. In the mutants, concomitant with the progressive shrinkage of the molecular layer, there was a progressive increase in the density of noradrenergic varicosities. This was most conspicuous at 9 and 12 months of age, at which time the molecular layer has been depleted not only of Purkinje cell dendrites, but also of parallel fibers. Noradrenergic fibers in these zones formed dense parallel bundles of varicose profiles whose density reached 621.3 +/- 122.8% (mean +/- SD, n = 4) at 9-12 months of age, compared with age-matched controls. Neurochemical measurement of norepinephrine content in whole cerebellum of the Purkinje cell degeneration mutants revealed no change compared with age-matched controls. We conclude that noradrenergic innervation persists in the cerebellar cortex despite the death of Purkinje cells and most of the granule cells. Although we found an increased density of varicosities in the molecular layer of mutant mice, progressing with age, we believe that this can be explained on the basis of the resultant geometry of the altered cerebellar cortex. It appears that the health of the environment surrounding the noradrenergic fibers in cerebellar cortex has little influence on their anatomical integrity.

Adrenergic Fibers↗