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PubMed2003

Physiology of cells in the central lobes of the mormyrid cerebellum.

The cerebellum of mormyrid electric fish is unusual for its size and for the regularity of its histology. The circuitry of the mormyrid cerebellum is also different from that of the mammalian cerebellum in that mormyrid Purkinje cell axons terminate locally within the cortex on efferent cells, and the cellular regions of termination for climbing fibers and parallel fibers are well separated. These and other features suggest that the mormyrid cerebellum may be a useful site for addressing some functional issues regarding cerebellar circuitry. We have therefore begun to examine the physiology of the mormyrid cerebellum by recording intracellularly from morphologically identified Purkinje cells, efferent cells, Golgi cells, and stellate cells in in vitro slices. Mormyrid Purkinje cells respond to parallel fiber input with an AMPA-mediated EPSP that shows paired pulse facilitation and to climbing fiber input with a large all-or-none AMPA-mediated EPSP that shows paired pulse depression. Recordings from the somas of Purkinje cells show three types of spikes in response to injected current: a small, narrow sodium spike; a large, broad sodium spike; and a large broad calcium spike. Efferent cells, Golgi cells, and stellate cells respond to parallel fiber input with an EPSP or EPSP-IPSP sequence and show only large, narrow spikes in response to intracellular current injection. We conclude that the physiology of the mormyrid cerebellum is similar in many ways to the mammalian cerebellum but is also different in ways that may prove instructive concerning the functional circuitry of the cerebellum.

Action Potentials↗
PubMed1988

Differential developmental expression of cellular yes and cellular src proteins in cerebellum.

To identify the specific areas of the brain that express c-yes and c-src proteins, we examined chicken brains dissected from two-week-old birds using an immune complex kinase assay and an immune blot analysis. Highest levels of both proto-oncogene proteins were found in the cerebellum, whereas other parts of the brain, including telencephalon, diencephalon, mesencephalon and spinal cord, showed three- to six-times lower levels. Relatively low levels of the two proteins were detected in pineal body and pituitary. When the cerebellum was further dissected into three layers, molecular, granular and fibrous, both the c-yes and c-src proteins were found to be concentrated in the molecular layer and, to a lesser degree, also in the granular layer. In cerebellum and in chicken embryo fibroblasts the c-yes protein was predominantly associated with the membrane fraction, and in chicken embryo fibroblasts c-yes was labeled with radioactive myristic acid. Adult cerebellum showed a two- to three-fold increase in the c-yes protein level over that detected in embryonal cerebellum. Conversely, c-src expression in the embryonic cerebellum was relatively high and it was diminished in the adult cerebellum. Differential developmental expression of c-yes and c-src proteins in cerebellum suggests that these proteins fulfill different functions or different aspects of the same function.

Age Factors↗
PubMed1993

Functional studies of the human cerebellum with positron emission tomography.

New techniques of functional imaging with PET have resulted in improved understanding of the organisation of the human brain at systems level. Many studies have concentrated on the organisation of the cerebral cortex, while the cerebellum has been subjected to less intensive investigations. In the motor system the contralateral cerebellum is intimately related to the functions of the primary motor cortex. This has been demonstrated in a number of studies involving simple and more complex motor activations. The relationship has also been demonstrated in pathology. The role of the cerebellum in the generation of tremor has been the subject of some considerable study with the demonstration of functional relationships between the olivary nucleus and the cerebellum as well as between the cerebellum, thalamus and motor cortex in essential and parkinsonian tremor. The cerebellum is also involved in motor learning. Parts of the motor system exhibit physiological adaptation during the repeated performance of a simple motor task. The cerebellum, in particular, shows a decrease in regional blood flow with practice of a motor task despite a similar performance. A number of recent reports suggest that the cerebellum is also involved in cognitive functions and particularly language. Functional neuroimaging has not addressed this problem explicitly; however, studies of severely depressed patients with cognitive impairments have shown an unexpected but interesting result in that impaired cognition but not the state of mind is associated with increases in cerebellar activity. The reason for the paucity of systematic investigations of cerebellar function has been the limited field of view, sensitivity and resolution of PET cameras.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1997

Glutamate-dependent activation of NF-kappaB during mouse cerebellum development.

NF-kappaB and activator protein 1 (AP-1) are dimeric transcription factors involved in transcriptional regulation in many cells, including neurons. We have examined their activity during mouse cerebellum development, a postnatal process starting just after birth and completed by the fourth postnatal (PN) week. The activity of these factors was analyzed by binding of nuclear extracts to a synthetic oligonucleotide representing the kappaB site of human immunodeficiency virus or the AP-1 site of the urokinase promoter. NF-kappaB activity was observed from 7 PN, was restricted to the developing cerebellum, and was not observed in the early postnatal neocortex and hippocampus. On the other hand, AP-1 activity was not found in cerebellum but was present in both neocortex and hippocampus. Moreover, a kappaB-driven transgene was found to be increasingly expressed in the cerebellum from 5 PN to 10 PN but not in the adult. The regulation of NF-kappaB activation in mouse cerebellum was analyzed by intraperitoneal injection of glutamate receptor antagonists to 9 PN mice, which abolished NF-kappaB-binding activity, suggesting an endogenous loop of glutamate receptor activation. Glutamate receptor agonists, on the other hand, induced NF-kappaB nuclear translocation in the cerebellum of 5 PN mice, which is a stage in which NF-kappaB is not yet endogenously activated. This effect was specific for NF-kappaB and not observed for AP-1. In adult mice, NF-kappaB activity was absent in the cerebellum and was not induced by intraperitoneal injection of glutamate receptor agonists. These data show that NF-kappaB is specifically activated during cerebellum development and indicate an important role of glutamate receptors in this process.

2-Amino-5-phosphonovalerate↗
PubMed2002

Toluene inhalation induces glial cell line-derived neurotrophic factor, transforming growth factor and tumor necrosis factor in rat cerebellum.

Rats were exposed to toluene (1500 ppm for 4 h per day) for 7 days. After toluene inhalation, only granule cells in the dentate gyrus of the hippocampus were slightly shrunken. In the cerebellum, several Purkinje cells were shrunken and lost, and the white matter was thinner than in controls. Microtubule-associated protein 2 (MAP2)-immunopositive filaments of neuronal processes were slightly disarrayed in the radial layer of the hippocampus, and were fragmented in the molecular layer of the cerebellum. It was considered that toluene induced neuronal changes both in the cerebellum and the hippocampus. To elucidate the effect of neurotrophic factors on those neuronal changes, glial cell line-derived neurotrophic factor (GDNF), transforming growth factor (TGF) and tumor necrosis factor (TNF) in rat brain were examined immunohistochemically. In control rats, TNF-alpha was not stained in either the hippocampus or the cerebellum, while TGF-beta1 was scarcely expressed in the cerebellum. GDNF was minimally expressed in the Purkinje cells in the cerebellum. After toluene-treatment, TGF-beta1 was over-expressed in the endothelium of the capillary vessel walls in both regions. In the cerebellum, TNF-alpha was induced only in the granule cells, while GDNF expression was enhanced in the Purkinje cells. These data suggest that toluene induces astrocyte activation through TGF-beta1 upregulation, which then induces GDNF in the Purkinje cells and TNF-alpha in the granule cells of the cerebellum. The differences in the expression of the neurotrophic factors may account for neurobehavioral changes after toluene exposure.

Journal Article↗
PubMed1996

Exencephaly and cleft cerebellum in SELH/Bc mouse embryos are alternative developmental consequences of the same underlying genetic defect.

SELH/Bc inbred mice have ataxia in 5-10% of young adults and exencephaly in 10-20% of newborns. SELH/Bc mice also have a high rate of spontaneous mutation and therefore it could not be assumed that these two abnormalities share the same genetic cause. Previously, we have shown that the liability to exencephaly in SELH/Bc mice is multifactorial, involving two to three loci, and that all the ataxics have a midline cleft cerebellum. The purpose of the present study was to resolve the genetic relationship between liability to exencephaly and liability to cleft cerebellum. We tested whether these traits were transmitted together by segregating F2 males; cotransmission would indicate that both traits are probably caused by the same genes. Approximately 100 embryos from each of 25 F2 sires from a cross between SELH/Bc and the normal LM/Bc strain were scored for exencephaly and the non-exencephalic embryos were scored for cleft cerebellum. The range of exencephaly production by these 25 F2 sires was 0% to 16%; the sires had been selected to represent the extremes of the range of exencephaly production. We found that the 10 sires that produced no exencephaly also produced no cleft cerebellum and 12 of the 15 sires that produced some exencephaly also produced some cleft cerebellum. This indicated strongly that the two traits are transmitted together (Fisher's exact test, P < 0.0002). Furthermore, within exencephaly-producing sires, the specific frequencies of the two traits were significantly positively correlated (Spearman rs = 0.58; P < 0.05), indicating that the same multifactorial risk factors influence both traits. All SELH/Bc embryos omit one normal initiation site of cranial neural tube closure, Closure 2. In a previous study, absence of the Closure 2 initiation site of cranial neural tube closure has been shown to be genetically correlated with liability to exencephaly. In the second part of the present study, the same Closure 2 data from eight of the F2 sires were observed to be significantly positively correlated with liability to cleft cerebellum (Spearman rs = 0.83; P < 0.05). The results of this genetic approach have supported the hypothesis, based on observation of embryos, that one basic multifactorial genetic defect in SELH mice leads to an abnormal cranial neural tube closure mechanism, to exencephaly to cleft cerebellum, and to ataxia.

Animals↗
PubMed1977

Experimental analysis of embryogenesis of cerebellum in rat. I. Subnormal growth following x-ray irradiation on day 15 of gestation.

Rat embryos of 15 days gestation were exposed in utero to 170 R of X-ray irradiation. Embryos collected 6 hours, 1, 2 and 3 days after irradiation, and animals of 2, 6, 15 and 30 days postnatal age were used for this study. Six hours after irradiation cells in the neuroepithelium and mantle layer along the roof of fourth ventricle were observed destroyed. Neuroepithelium showed only fragmentary regeneration during next two days, and it contributed to a small number of Purkinje cells. During postnatal development of cerebellum the external granular layer, the zone of proliferative cells that gives rise to neurons of postnatal origin, was found reduced. Other structures such as internal granular layer, molecular layer and medullary layer also were reduced. These multiple temporally sequenced developmental events resulted in a subnormal-sized cerebellum. Various quantitative measures helped establish that grossly the cerebellum in the X-ray irradiated animals was about half of that in the normal animals. Problems related to regeneration in the embryonic cerebellum, and to the factors determining the subnormal size of the adult cerebellum are discussed. Viewing this as an experimental approach to the study of neuroembryogenesis of cerebellum, the role of Purkinje cells in the regulation of development of cerebellum is brought out.

Animals↗
PubMed2006

Evidence for the presence of the type 2 corticotropin releasing factor receptor in the rodent cerebellum.

Corticotropin releasing factor (CRF), localized in afferent inputs to the cerebellum, binds to two receptors defined as the Type 1 (CRF-R1) and the Type 2 (CRF-R2alpha). CRF-R1 has been localized to the cerebellum, as has a truncated isoform of CRF-R2alpha. Evidence for the presence of the full length isoform of CRF-R2alpha in the cerebellum is conflicting. We used RT-PCR, immunohistochemical, and physiologic techniques to resolve this conflict. RT-PCR data show low levels of CRF-R2alpha in the vermis and hemisphere of the cerebellum. These observations were confirmed by the Gene Expression Nervous System Atlas (GENSAT) database. A CRF-R2alpha antibody was used to determine the cellular distribution of the receptor in the cerebellum. The vast majority of the receptors are localized to Bergmann glial cells located throughout the cerebellum, as well as astrocytes in the granule cell layer. Neuronal labeling is present in sub-populations of Purkinje cells, Golgi cells, basket cells, and cerebellar nuclear neurons. Physiologic data show that urocortin II, which binds selectively to CRF-R2alpha, increases the firing rate of both Purkinje cells and nuclear neurons; this response can be blocked by the CRF-R2alpha-specific antagonist, antisauvagine-30. The present results confirm that CRF-R2alpha is present in the cerebellum and functions in circuits that modulate the firing rate of Purkinje cells and cerebellar nuclear neurons. A comparative analysis showed that the patterns of distribution of CRF-R1, CRF-R2alpha and CRF-R2alpha-tr are distinct. These data indicate that the CRF family of peptides modulates cerebellar output by binding to multiple CRF receptors.

Animals↗
PubMed2001

The lateralized linguistic cerebellum: a review and a new hypothesis.

During the past 2 decades the collaboration across disciplines and the methodologic and conceptual advances of contemporary neuroscience have brought about a substantial modification of the traditional view of the cerebellum as a mere coordinator of autonomic and somatic motor functions. Growing insights in the neuroanatomy of the cerebellum and its interconnections, evidence from functional neuroimaging and neurophysiological research, and advancements in clinical and experimental neuropsychology have established the view that the cerebellum participates in a much wider range of functions than conventionally accepted. This increase of insight has brought to the fore that the cerebellum modulates cognitive functioning of at least those parts of the brain to which it is reciprocally connected. This article reviews the recently acknowledged role of the cerebellum in cognition and addresses in more detail experimental and clinical data disclosing the modulatory role of the cerebellum in various non-motor language processes such as lexical retrieval, syntax, and language dynamics. In agreement with the findings indicating a topographical organization of the cerebellar structures involved in language pathology we advance the concept of a "lateralized linguistic cerebellum." In our view crossed cerebral diaschisis processes, reflecting a functional depression of supratentorial language areas due to reduced input via cerebellocortical pathways, might represent the relevant pathomechanism for linguistic deficits associated with cerebellar pathology.

Aphasia↗
PubMed1996

Reversible inactivations of the cerebellum with muscimol prevent the acquisition and extinction of conditioned nictitating membrane responses in the rabbit.

Lesions of the cerebellum severely impair the classically conditioned nictitating membrane response (NMR) in rabbits. Thus, the cerebellum is essential for the production of conditioned responses (CRs), either because it is actively involved in NMR conditioning or because damage to it causes motor or other general deficits. To distinguish between these alternatives, the cerebellum may be inactivated during training. Inactivation of the cerebellum during acquisition training might result in the absence of CRs on initial trials of subsequent training without the neuronal blockade. The blockade may have prevented learning but it may have produced other deficits that require time or further training to overcome. This problem can be addressed by inactivating the cerebellum during extinction training. If inactivation during extinction training results in the immediate production of CRs when training is resumed without the blockade, then it may be concluded that extinction learning was prevented by the blockade-the presence of CRs argues against any deficits not associated with learning. We used muscimol to inactivate the cerebellum and test its involvement in acquisition and extinction of NMR conditioning in the same subjects. We injected muscimol close to the interpositus nucleus of the cerebellum 1 h before each of four daily training sessions of delay conditioning. Almost no CRs were produced in these training sessions-there was little or no acquisition of NMR conditioning during cerebellar inactivation. The subjects were then trained for four daily sessions without injections of muscimol. There were no CRs on initial trials of the first session of retraining, but all subjects produced CRs by the end of this session. The subjects then received four daily sessions of extinction training with muscimol inactivation of the nuclei-no CRs were produced. Extinction training then continued for four daily sessions without muscimol inactivation. On the first of these sessions, all subjects immediately produced high levels of CRs. These responses then extinguished within and between sessions with characteristic beginning-of-session spontaneous recovery. There was little or no extinction of NMR conditioning during cerebellar inactivation. After inactivation, the muscimol- inactivated subjects went on to acquire and extinguish NM responses at rates similar to those of appropriate controls. We conclude that cerebellar circuitry is essential for, and actively engaged in, both acquisition and extinction of this simple form of motor learning.

Animals↗
PubMed1988

A temporal analysis of the origin and distribution of serotoninergic afferents in the cerebellum of pouch young opossums.

In the present study, a temporal analysis of the pattern of distribution of serotoninergic fibers and varicosities within the cerebellum of pouch young opossums was carried out. Particular attention was focused on animals ranging in age from postnatal day (PD) 21-PD 72, because there is a transient expression of serotonin immunoreactivity in the cerebellar cortex during that interval. Between PD 1-33, there is a progressive increase in serotoninergic immunoreactivity throughout the cerebellar cortex. After PD 33, there is a decrease in the relative number of immunostained fibers followed by a reorganization into the adult pattern of distribution. A double labeling paradigm, in which horseradish peroxidase, used as a retrograde marker, combined with serotonin immunohistochemistry was employed to localize serotoninergic neurons that project to the developing cerebellum. Initially (PD 9), serotoninergic cells in the medullary reticular formation and dorsolateral pontine tegmentum are double labeled. After PD 77, only neurons in the medullary reticular formation were double labeled. The course taken by serotoninergic axons from the brainstem to the cerebellum also was analyzed. Between PD 1 and PD 42, serotoninergic axons enter the cerebellum via four different routes: 1) the inferior cerebellar peduncle; 2) a pathway located lateral and rostral to the inferior cerebellar peduncle; this bundle of serotonin axons contains immunoreactive fibers that also enter the tectum (this tract is referred to as the tecto-cerebellar bundle in this report); 3) the medial aspect of the superior cerebellar peduncle; and 4) the tela choroidea. After PD 40, the latter two pathways are the primary routes by which serotoninergic fibers enter the cerebellum. The loss of serotoninergic fibers in the first two pathways coincides with the decrease in serotoninergic immunoreactivity seen in the cerebellar cortex described above. In summary, the results suggest that the serotoninergic projection to the opossum's cerebellum is remodelled during development. It is proposed that the serotonin fibers present at early stages of development may play a role in regulating specific events in cerebellar maturation. In contrast, the serotoninergic axons which have a more restricted pattern of distribution later in development, and in the adult, likely modulate neuronal activity within the cerebellum.

Afferent Pathways↗
PubMed1985

An immunohistochemical study of serotonin development in the opossum cerebellum.

In the present study we have used the indirect antibody peroxidase anti-peroxidase technique to analyze the development of serotonin in the cerebellum of pouch young opossums ranging in age from birth (postnatal day (PD) 1) - to PD 47. The pathways by which serotoninergic axons enter the cerebellum appear to change during development. Between PD 1 and PD 11 varicose serotoninergic fibers course though the continuity between the tectum and the dorsal medial aspect of the cerebellar plate and distribute primarily to the intermediate zone. By PD 11 serotoninergic fibers enter the cerebellum via a connecting band between the cerebellum and the dorsal lateral aspect of the rostral medulla. Fibers entering the cerebellum via this later route course around the lateral recess of the fourth ventricle and initially distribute to ventral and lateral areas of the cerebellum. At later developmental ages (PD 14-PD 47) serotoninergic fibers are present in: 1) the cellular zone of migration between the Purkinje cell layer and deep nuclei; 2) the Purkinje cell layer; 3) the internal granule cell layer; and 4) the deep cerebellar nuclei. The external granule cell and the molecular layers rarely contain serotoninergic fibers. The present study has shown that serotonin is present in the cerebellar anlage on PD 1 (within 13 days of conception). This is prior to the arrival of other major afferent systems (King et al. 1982; Bishop et al. 1983; Martin et al. 1983; Morgan et al. 1983). Further, serotoninergic axons reach the cerebellum via different routes at different stages of development. The presence of serotonin in the intermediate zone early in development supports the hypothesis that it may influence neuronal migration and differentiation (Lauder and Krebs 1976). Axons containing serotonin and arriving later in development may function in synaptic transmission, a role proposed for this indoleamine in the adult (Strahlendorf et al. 1979).

Animals↗
PubMed1986

Quantitative detection of DNA damage in the neuronal cells of the cerebellum and cerebrum by the analysis of Feulgen hydrolysis curves.

Touch smears of the cerebellum and cerebrum of ageing rats were fixed with methanol, hydrolyzed with 2 N HCl at various temperatures and for various periods, and stained with pararosaniline-Schiff reagent. The hydrolysis curves were determined by fluorescence cytophotometry and were computer fitted to the Bateman function to determine the kinetic parameters, the initial yield of apurinic acid or single-stranded DNA (y0), and the rate constants for depurination or denaturation (k1) and depolymerization (k2). The values for k1 (1/k1 is correlated with the degree of chromatin condensation) and k2 (which reflects the degree of DNA instability) steadily increased with age. The values for y0, which may indicate the degree of DNA denaturation or damage present before acid hydrolysis, also increased with age in both the cerebellum and cerebrum; however, this value was lower in the cerebellum until 15 weeks, with the situation being reversed after 35 weeks, the cross-over time being at about 25 weeks. The values of lnk1 and lnk2 were plotted as the function of the reciprocal of the absolute temperature (T) (Arrhenius plot) for both the cerebellum and cerebrum of 15- and 74-week-old rats, and the activation energies (E) for depurination and depolymerization were calculated from the slopes. In particular, the values of E for k2 decreased much more quickly with age and were smaller in cerebellum. In conclusion, the degree of DNA damage and DNA instability steadily increases in both the cerebellum and cerebrum of ageing rats, and this process is much faster in the cerebellum.

Aging↗
PubMed2003

Constitutive and inducible levels of CYP1A1 and CYP1A2 in rat cerebral cortex and cerebellum.

We examined the constitutive and inducible levels of microsomal cytochromes P450 1A1 and 1A2 (CYP1A) in rat cerebral cortex and cerebellum at the level of proteins by western blot analysis, and by catalytic activities via ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-demethylase (MROD). In the cerebral cortex, cytochrome P450 1A1 (CYP1A1) protein was more abundant than cytochrome P450 1A2 (CYP1A2) protein. Treatment with beta-naphthoflavone (beta-NF) caused a slight decrease in the level of the former but induced the latter 5.8-fold. In the cerebellum, in contrast to the cerebral cortex, CYP1A1 protein was less abundant than CYP1A2 protein in untreated rats, and while beta-NF treatment caused a 3.3-fold induction of CYP1A1 protein, it resulted in a 10-fold decrease in CYP1A2 protein. The CYP1A-preferential activity EROD was 2.3-fold higher in the cerebellum than in the cerebral cortex, and was induced 1.5-fold and 1.9-fold in the cerebellum and cerebral cortex, respectively, by beta-NF treatment. The CYP1A2-preferential activity MROD was 3-fold higher in the cerebellum than in the cerebral cortex, and was repressed 2.2-fold in the cerebellum but induced 3.7-fold in the cerebral cortex following beta-NF treatment. The results show that CYP1A1 and CYP1A2 proteins and catalytic activities are constitutively expressed in brain but are differentially inducible in the rat cerebral cortex and cerebellum.

Animals↗
PubMed1980

The effects of sex and neonatal androgenization on thymidine kinase activity and DNA content in the cerebellum of the rat.

The effects of neonatally administered testosterone propionate (TP) were determined on the activity of thymidine kinase and on the content of DNA in the cerebellum of the rat during early postnatal development. Forty-eight hours after birth, female and male pups were injected s.c. with either 1.5 mg TP or an equivalent volume of vehicle. Cerebellar thymidine kinase activity and DNA content were measured at 3, 4, 6, 7, 8, 10, 12, 15, 18 and 21 days of age. A sexual dimorphism in thymidine kinase activity was found for control rats between 6 and 18 days of age, i.e. the activity of the enzyme was significantly higher in the cerebellum of the female controls. The activity of thymidine kinase in the cerebellum of TP-treated male rats was significantly greater than that of the male controls between 4 and 21 days of age. The activity of thymidine kinase in the cerebellum of TP-treated female pups was significantly lower than that of the female controls between 6 and 12 days of age. Enzyme activity at age 15 days was the same for TP-treated and control female rats. However, thymidine kinase activity in the cerebellum of TP-treated female rats was significantly increased above that of the controls at 18 and 21 days of age. Thus, the response of the enzyme following the injection of TP 48 h after birth was sex-dependent between 4 and 15 days of age. Alterations in cerebellar DNA content in the TP-treated male and female rats closely paralleled the changes described for thymidine kinase. These data suggest sex-dependent transactions between the animal and the injection of TP as well as androgen-dependent relationships between thymidine kinase and DNA synthesis in the cerebellum. Significant changes in the Michaelis-Menten constant with increasing age also suggest that the developing cerebellum contains more than one form of the enzyme.

Animals↗
PubMed1991

Peptide heterogeneity of GABAA/benzodiazepine receptors in bovine cerebral cortex and cerebellum.

The GABAA/benzodiazepine receptor complex has been purified from both bovine cerebral cortex and cerebellum by immunoaffinity chromatography on immobilized monoclonal antibody 62-3G1. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the purified receptor from either cerebral cortex or cerebellum revealed 3 main bands corresponding to 51,000, 55,000 and 57,000 Mr silver-stained peptides. In addition, a minor band corresponding to a 53,000 Mr peptide was also found. The differences between the two receptor preparations were: (1) that the main silver-stained 55,000 Mr subunit was present in a relative smaller quantity in cerebellum than in cerebral cortex, and (2) when the membrane-bound receptor was photoaffinity-labeled with [3H]flunitrazepam and subsequently immunoaffinity-purified, two photolabeled peptide bands of 51,000 and 57,000 Mr were found in cerebral cortex while only the 51,000 Mr photolabeled peptide was detected in cerebellum following one-dimension sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Peptide maps of the 57,000 Mr [3H]flunitrazepam photoaffinity-labeled peptide indicated that it was composed of two closely migrating photolabeled peptides of 55,000 Mr and 57,000 Mr. Peptide mapping and deglycosylation experiments using the [3H]flunitrazepam photolabeled receptor suggested that the photolabeled peptides commonly present in cerebellum and cerebral cortex are qualitatively similar if not identical. The results suggest that there are subunits of some type(s) of GABAA R/BZDR complex(es) which are more abundant in cerebral cortex than in cerebellum. Photoaffinity labeling with [3H]muscimol showed similar photolabeled peptides in both cerebral cortex and cerebellum: two main peptides of 54,000 and 57,000 Mr were photolabeled with [3H]muscimol to a similar extent in both receptor preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Delayed detyrosination of alpha-tubulin from parallel fibre axons and its correlation with impaired synaptogenesis in hypothyroid rat cerebellum.

The biochemical basis of retarded differentiation and maturation of microtubules and impaired synaptogenesis in hypothyroidism has been investigated by studying the temporal and spatial relationship between alpha-tubulin detyrosination in the parallel fibre axons of rat cerebellum and alterations in the activity of the detyrosinating enzyme, TTCP (tubulinyl tyrosine carboxypeptidase) with the progress of synaptogenesis in the molecular layer. Detyrosination was monitored by following the disappearance of stain from cerebellar sections, immunocytochemically labeled with a monoclonal antibody (20C6) specific for alpha-tubulin, tyrosinated at the C-terminal end. With respect to normal controls, detyrosination of alpha-tubulin from the parallel fibres of the molecular layer during synaptogenesis was not only delayed by about 5 days but also prolonged in the hypothyroid cerebellum. Correspondingly, the increase of TTCP activity in the developing thyroid deficient cerebellum was also delayed by about 1 week. Comparison of the developmental profile of TTCP activity in the normal and hypothyroid cerebellum during synaptogenesis revealed that the overall activity of the enzyme in the thyroid deficient cerebellum was reduced to almost half of that of the normal controls. These results establish that thyroid hormones are essential for the induction of TTCP, which catalyses detyrosination during the normal ontogenic development of rat cerebellum. Since our data also suggest that detyrosination precedes synaptic contacts to generate a class of differentiated microtubules functionally competent for synaptogenesis, the delayed detyrosination in the hypothyroid cerebellum may desynchronize the normal developmental program resulting in incomplete synaptogenesis.

Aging↗
PubMed1982

Ontogeny of somatostatin-containing neuron system of the rat cerebellum including its fiber connections: an experimental and immunohistochemical analysis.

Ontogeny of somatostatin (SRIF) neuron system of the rat cerebellum was investigated by means of the indirect immunofluorescent method. In addition, several operations were performed to provide the evidence of understanding the cerebellar SRIF innervation. SRIF-positive structures appeared in the primordium of the cerebellum of the fetus at gestational day 16 (14-15 mm embryos). From that time on, SRIF-positive structures identified in the cerebellum increased in number and the greatest number of SRIF-positive structures were detected in the cerebellum of the rat between newborn and 7-day-olds. Afterwards, these structures decreased remarkably in number and only a few if any SRIF-positive structures were observed in the cerebellum of the adult rats. These facts might suggest that SRIF might perform some important roles in the development of the cerebellum. The present study further elucidated that cerebellar SRIF was supplied by at least two types of sources; one was situated within the cerebellum and the other in the extracerebellar regions. The former one innervates mainly the vermis and partly the hemisphere, while the latter one projects mainly to the hemisphere and partly to the vermis.

Aging↗