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PubMed2005

Dopamine D3 modulation of locomotor activity and sleep in the nucleus accumbens and in lobules 9 and 10 of the cerebellum in the rat.

Dopamine D3 receptors are present in the nucleus accumbens and in lobules 9 and 10 of the cerebellum. Their function is not fully understood. In the present study, the involvement of D3 receptors in locomotor activity and sleep in the two structures was investigated. The method used was the measure of locomotor activity in an open field and the measure of sleep and sleep/waking stages by electroencephalographic recordings in the rat. Dopamine receptor agonists (7-OH-DPAT, quinelorane and SKF38393) and antagonists (amisulpride, nafadotride and haloperidol) were microinjected into the two structures. Concerning locomotor activity, the results show that D3 receptor stimulation, as well as concomitant stimulation of D1 and D3 receptors, have opposite effects in the cerebellum and in the core of nucleus accumbens, with an inhibition of locomotion in the cerebellum and a stimulation of locomotion in the nucleus accumbens. D1 and D3 stimulation have mutual potentiating locomotor effects. The results also show that in the cerebellum, the effects are selective to lobules 9 and 10, and are not observed with microinjections into lobule 8. Concerning sleep, the effects of agonists and antagonists show a similar tendency in the cerebellum and nucleus accumbens, with a somnogenic effect of D2 blockage, an awakening effect of at least one of the D2/D3 agonists, and a dose-dependent awakening effect of the D2/D3 antagonists. In conclusion, this study suggests that dopamine D3 receptors in the cerebellum and nucleus accumbens are involved in several aspects of the regulation of locomotor activity and sleep.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2006

Cerebellum progesterone concentration decreased in canine distemper virus infection.

Progesterone has neuroprotective effects including augmentation of myelination in the central and peripheral nervous system. This study was designed to determine if demyelinating lesions in the cerebellum resulting from canine distemper virus (CDV) infection are associated with progesterone levels. Progesterone was measured using radioimmunoassay in samples of the cerebellum, corpus callosum, medulla oblongata, parietal, frontal, temporal, and occipital cortices as well as cerebrospinal fluid (CSF) and plasma collected from ten CDV infected and six non-infected dogs. The cerebellum progesterone level was significantly different between CDV infected (0.66+/-0.09 ng/g) and control dogs (1.14+/-0.09 ng/g) (p<0.001); however, no difference was observed for the other CNS regions, plasma and CSF (p>0.05). The cerebellum progesterone level was also significantly different between acute (0.71+/-0.0 5 ng/g) and chronic cases (0.61+/-0.09 ng/g) (p<0.05). The CDV infected cerebella were also categorized histopathologically according to the severity of demyelinating lesions as mild (n=5), moderate (n=2), or severe (n=3) among which the cerebellum progesterone level was significantly different (p<0.05). Progesterone concentration was 0.71+/-0.05 ng/g in mild, 0.65+/-0.10 ng/g in moderate, and 0.56+/-0.07 ng/g in severe cases. In conclusion, progesterone concentration decreases in the cerebellum in CDV infection and the severity of demyelinating lesions is the greatest in cerebella with the lowest progesterone concentrations. The results suggest that local impairment of progesterone metabolism may be associated with the initiation and progression of cerebellar lesions in CDV infection.

Animals↗
PubMed1998

The effects of simulated ischemia on the levels of adenosine and its metabolites in slices of cerebellum, superior colliculus and hippocampus in the guinea pig-in vitro study.

The purpose of this present study is to clarify adenosine (ADO) metabolism in guinea pig brain slices during simulated ischemia. In slice preparations after decapitation, ADO levels were lowest in slices of the cerebellum (1.2 nmol/mg protein), followed by the superior colliculus (3.4) and highest in the hippocampus (6.4), and the combined concentrations of inosine (Ino) and hypoxanthine (HX) were highest in the cerebellum (5.5), followed by the superior colliculus (3.5) and the hippocampus (1.5). After preincubation with standard medium with oxygen and glucose for 30 min, total ADO levels (tissue ADO plus ADO lost into medium during incubation) decreased to 0.3 in the cerebellum, to 1.3 in the superior colliculus and to 2. 9 in the hippocampus. On the other hand, levels of total Ino and HX increased to 21.1 in the cerebellum, to 14.3 in the hippocampus and to 12.0 in the superior colliculus. To investigate the effect of simulated ischemia on ADO metabolism, preincubated slices were exposed for 10 min in medium deprived of oxygen and glucose. The increases of ADO content after 10 min ischemia were 0.2 in the cerebellum, 1.0 in the superior colliculus and 1.3 in the hippocampus. In contrast, the increases of both Ino and HX concentrations were 2.9 in the cerebellum, 2.2 in the superior colliculus and 1.4 in the hippocampus. The total amount of the increase in ADO, Ino and HX was approximately 3 in all three regions. These results indicate that there are significant differences in the metabolic rate to degrade ADO into Ino and HX in various areas of brain possibly due to differences in adenosine deaminase activity in those areas.

Adenosine↗
PubMed1997

Sensory nociceptive axons invade the cerebellum of transgenic mice overexpressing nerve growth factor.

Transgenic mice possessing elevated levels of mRNA expression and synthesis for the neurotrophin nerve growth factor among astrocytes display a robust ingrowth of new sympathetic fibers to the cerebellum. In this investigation, we report that the cerebellum of these mice also possesses a dense plexus of aberrant axons of sensory origin. Axons stained immunohistochemically for calcitonin gene-related peptide were seen in the transgenic cerebellum as early as one week after birth. The density of these axons dramatically increased with age. Immunopositive axons were confined predominantly to the deep white matter of the cerebellum in the adult transgenic mice, with a smaller number of axons seen coursing along blood vessels in the gray matter. Axons stained immunohistochemically for the neurotrophin receptor, p75NTR, displayed a similar pattern of distribution and density as those immunostained for calcitonin gene-related peptide. Wild-type post-natal and adult animals lacked such calcitonin gene-related peptide- and p75NTR-immunoreactive axons in the cerebellum. Retrograde labelling revealed that these axons within the transgenic cerebellum originated from neurons in the sensory trigeminal and dorsal root ganglia (upper cervical levels). This investigation demonstrates that overexpression of nerve growth factor is capable of inducing the directional growth of collateral axons of sensory neurons into the undamaged mammalian central nervous system.

Animals↗
PubMed2000

Total mercury in human renal cortex, liver, cerebellum and hair.

The aim of this study was: (a) to estimate the concentration of total mercury in the renal cortex, liver, cerebellum and hair of 46 persons who died suddenly in the Gdańsk region, northern Poland, between the ages of 17 and 90; and (b) to assess whether a correlation occurs between mercury content in the investigated biological media. The mean concentrations of mercury in the human hair, renal cortex, liver and cerebellum were: 378 +/- 315.4 ng/g; 68.6 +/- 92.3 ng/g; 29.9 +/- 22 ng/g and 5.3 +/- 6.9 ng/g respectively. Positive correlations were found between mercury levels in: cerebellum and liver (r = 0.873), cerebellum and hair (r = 0.853), cerebellum and renal cortex (r = 0.578), hair and liver (r = 0.771), hair and renal cortex (r = 0.478) liver and renal cortex (r = 0.66). The geometric mean levels of mercury in the renal cortex, liver, cerebellum and hair in the residents of the Gdańsk region are 15-19 times lower than in the population of Tokyo and its environs [Suzuki T, Hongo T, Yoshinaga J et al. The hair-organ relationship in mercury concentration in contemporary Japanese. Arch Environ Health 1993;44:361-365].

Adolescent↗
PubMed1997

Cholinergic innervation and receptors in the cerebellum.

We have studied the source and ultrastructural characteristics of ChAT-immunoreactive fibers in the cerebellum of the rat, and the distribution of muscarinic and nicotinic receptors in the cerebellum of the rat, rabbit, cat and monkey, in order to define which of the cerebellar afferents may use ACh as a neurotransmitter, what target structures are they, and which cholinergic receptor mediate the actions of these pathways. Our data confirm and extend previous observations that cholinergic markers occur at relatively low density in the cerebellum and show not only interspecies variability, but also heterogeneity between cerebellar lobules in the same species. As previously demonstrated by Barmack et al. (1992a,b), the predominant fiber system in the cerebellum that might use ACh as a transmitter or a co-transmitter is formed by mossy fibers originating in the vestibular nuclei and innervating the nodulus and ventral uvula. Our results show that these fibers innervate both granule cells and unipolar brush cells, and that the presumed cholinergic action of these fibers most likely is mediated by nicotinic receptors. In addition to cholinergic mossy fibers, the rat cerebellum is innervated by beaded ChAT-immunoreactive fibers. We have demonstrated that these fibers originate in the pedunculopontine tegmental nucleus (PPTg), the lateral paragigantocellular nucleus (LPGi), and to a lesser extent in various raphe nuclei. In both the cerebellar cortex and the cerebellar nuclei these fibers make asymmetric synaptic junctions with small and medium-sized dendritic profiles. Both muscarinic and nicotinic receptor could mediate the action of these diffuse beaded fibers. In the cerebellar nuclei the beaded cholinergic fibers form a moderately dense network, and could in principle have a significant effect on neuronal activity. For instance, the cholinergic fibers arising in the PPTg may modulate the excitability of the cerebellonuclear neurons in relation to sleep and arousal (e.g. McCormick, 1989). Studies on the distribution of cholinergic markers in the cerebellum have proven valuable besides the issue whether cholinergic mechanism play a role in the cerebellar circuitry, because they illustrate a complexity of the cerebellar anatomy that extends beyond its regular trilaminar and foliar arrangement. For instance, AChE histochemistry has been shown to preferentially stain the borders of white matter compartments (the 'raphes', Voogd, 1967), and therefore is useful in topographical analysis of the cortico-nuclear and olivocerebellar projections (Hess and Voogd, 1986; Tan et al., 1995; Voogd et al., 1996; see Voogd and Ruigrok, 1997, this Volume). ChAT-immunoreactivity, at least in rat, appears to be a good marker to outline the morphological heterogeneity of mossy fibers, and m2-immunocytochemistry could be used to label (subpopulations of) Golgi cells, subsets of mossy fibers and, in the rabbit, a specific subset of Purkinje cells (Jaarsma et al., 1995).

Acetylcholine↗
PubMed1997

Differential expression of calretinin, calbindin D28K and parvalbumin in the developing human cerebellum.

Three calcium-binding proteins, calretinin, calbindin D28K and parvalbumin, were immunohistochemically localized in the human cerebellum at different developmental stages. Cells positive for calretinin were not detected during early development of the cerebellum until 21 weeks of gestation at which stage weak staining was found in Purkinje and basket cells of the cortex and in neurons of the dentate nucleus. Both the number of positive cells and the intensity of immunoreactivities were found to increase as the cerebellum became more mature. Calbindin D28K immunoreactivity was, however, detected early in development at 14 weeks of gestation. Positive cells were found in Purkinje, basket, stellate and granule cells of the cerebellar cortex and in neurons of fastigial, globose, emboliform and dentate nuclei. The number of positive cells and the staining intensity for calbindin in both the cerebellar cortex and deep nuclei decreased at more advanced developmental stages. At 21-31 weeks of gestation, positive staining was restricted to Purkinje and basket cells of the cortex. Parvalbumin immunoreactivity was also observed early in development at 14 weeks of gestation. Positivity was found in Purkinje, basket and stellate cells of the cerebellar cortex and in neurons of all the deep nuclei, with the highest number of positive cells in the fastigial nucleus followed by emboliform, globose and dentate nuclei. As the cerebellum became more mature, both the number of positive cells and the staining intensity for parvalbumin decreased in the cortex and deep nuclei. The results of the present study showed that among the three calcium-binding proteins examined, strong immunoreactivities for calbindin D28K and parvalbumin were found inthe human cerebellum early in development at 14 weeks of gestation, but there was a decrease in both the intensity and number of positive cells at more advanced stages. In contrast, calretinin positive cells were not detected until 21 weeks of gestation and the immunoreactivity increased as the cerebellum became more mature. A possible correlation between the developmentally regulated expression of the calcium-binding proteins and expression of different neurotransmitters during development is discussed.

Abortion, Induced↗
PubMed1999

Developmental expression of corticotropin-releasing factor in the postnatal murine cerebellum.

Corticotropin-releasing factor (CRF) is present in climbing and mossy fibers and both have a distinct pattern of distribution in the adult cerebellar cortex. The intent of this developmental study is to determine when the lobular pattern of CRF distribution emerges, and to analyze the morphogenesis of CRF immunoreactive climbing and mossy fibers in individual cerebellar lobules. Between postnatal day (P)0 and P3, CRF-immunoreactive (IR) punctate elements are present throughout the cerebellum. By P3, there is a decrease in the density of staining in the white matter and punctate elements become concentrated within the developing cortex. Between P3 and P7 CRF-IR, varicosities circumscribe Purkinje cell bodies, and are present in the internal and external granule cell layers. Between P10 and P12, there is a major reduction in the density of CRF-IR puncta, especially in the internal and external granule cell layers. Varicosities remain around Purkinje cell bodies and some extend into the molecular layer. During this interval, CRF-IR profiles are first evident in axonal configurations characteristic of developing climbing fibers, although there are lobular differences in the degree of maturation of this afferent system. Axonal enlargements characteristic of immature mossy fibers can first be seen at P10 in lobules IX and X; they cannot be differentiated until P12-14 in more rostral or lateral lobules. CRF-IR fibers in lobules IX and X, the vestibulocerebellum, develop into mature climbing and mossy fibers before any other area of the cerebellum. In other lobules of the cerebellum the gradient of maturation for these axonal phenotypes is from medial to lateral and posterior to anterior. Between P10 and P12, CRF-IR climbing fibers are present in all lobules of the cerebellum. After P12, few climbing fibers are observed in the anterior lobe of the cerebellum at midvermal levels; those present are only faintly immunolabeled. Based on its early expression and uniform distribution between P0 and P10, CRF could have a role in cerebellar development. After this age, as climbing and mossy fiber terminal phenotypes mature, and the differential adult patterns of distribution emerge, CRF likely begins to function as a neuromodulator as has been shown in the adult cerebellum.

Animals↗
PubMed1997

Magnetic stimulation over the cerebellum in patients with ataxia.

We studied 20 patients with ataxia caused by various disorders using magnetic stimulation over the cerebellum. Results were compared with normal values found for 12 normal volunteers. In normal subjects, a magnetic stimulus over the cerebellum reduced the size of responses evoked by magnetic cortical stimulation when it preceded cortical stimulus by 5, 6 and 7 ms. The grand average of the ratios of the areas of conditioned responses at intervals of 5, 6 and 7 ms to those of control responses was designated the average area ratio (5-7 ms). Suppression of motor cortical excitability was reduced or absent in patients with a lesion in the cerebellum or cerebellothalamocortical pathway, but was normal in patients with a lesion in the afferent pathway to the cerebellum. Normal suppression was observed in Fisher's syndrome. The average area ratio (5-7 ms) correlated well with the severity of ataxia in patients with degenerative late-onset ataxia. These results are consistent with those for electrical stimulation of the cerebellum reported previously. We conclude that magnetic stimulation over the cerebellum produces the same effect as electrical stimulation even in ataxic patients. This less painful method can be used clinically to clarify the pathomechanisms for ataxia. Two other clinical uses of this technique were that it revealed clinically undetectable cerebellar dysfunction in patients whose extrapyramidal signs masked cerebellar signs, and that the slow progression of ataxia could be followed quantitatively in patients with degenerative late-onset ataxia.

Adult↗
PubMed2003

The cyclin-dependent kinase 5 activator, p39, is expressed in stripes in the mouse cerebellum.

Cyclin-dependent kinase 5 (Cdk5) activity is required for CNS development. The Cdk5 activator, p35, is well characterized but its isoform, p39, has been less studied. Previously, p39 mRNA expression in rat brain was shown to peak at 3 weeks postnatal, and the level remains high in the adult cerebellum [Neurosci Res 28 (1997) 355]. However, p39 protein expression and specific localization in the cerebellum, where p39 mRNA level significantly exceeds that of p35, have not been examined. Here, we explored the specific cerebellar localization of the p39 protein in the developing and adult mice. Adult cerebellar Purkinje cell somata and dendritic arbors were strongly positive for p39 but only rare and barely detectable p39 was observed in Purkinje cell axons. Cdk5 also localized in Purkinje cell somata and dendrites of the adult cerebellum, but p35 localized only in Purkinje cell somata, further suggesting a functional difference between p35 and p39. During development, cerebellar p39 was first noted at P10. Primary cultures of a developing cerebellum also showed strong p39 immunoreactivity in Purkinje cell somata and dendrites, but weak p39 immunoreactivity in Purkinje cell axons. Starting from P10, p39 was observed in a subset of Purkinje cells that form parasagittal bands throughout the vermis and hemispheres. These bands were bilaterally symmetrical and continuous from one lobule to another. Conversely, Cdk5 and p35 showed a uniform staining pattern. The pattern of p39 closely resembled that of zebrin II/aldolase C, suggesting that p39 may play a role in the adult cerebellum rather than in pattern development. This premise is consistent with the normal pattern of zebrin II/aldolase C zones and stripes in mutant p39-/- mice. The alternating p39 parasagittal band pattern may reflect a role for p39 or Cdk5/p39 in the functional compartmentation of the cerebellum.

Animals↗
PubMed2002

Sexual dimorphism in rat cerebrum and cerebellum: different patterns of catalytically active creatine kinase isoenzymes during postnatal development and aging.

During postnatal development, maturation and aging the Wistar rat cerebrum and cerebellum synthesize, in a different sex-dependent manner, catalytically active dimeric cytosolic (c) muscle-type (MM) and heart-type (MB) creatine kinase (CK), besides the supposedly sole type brain-specific (BB) CK. In both sexes, typical and atypical neuromuscular cCK isoenzymes were present during the study for 26 months. As in rat heart, females showed more cerebral cCK variants (41%) in comparison to males. Female rats exhibited about 93% more cerebellar variants of cCK isoenzymes as compared to males. The male cerebellum showed predominantly BB- and MB-CK during the whole study in comparison to the female one that contained all neuromuscular cCK variants. Only female rats showed decreases and increases of cerebral CK specific activity. In contrast to males, coinciding with the weaning period, cerebral female CK activity decreased 45% from 14 to 21 days and increased about 3-fold in female rats and only 1.3-fold in males from 21 to 45 days of age. Contrary to the remarkable 4-fold increase of chicken brain CK specific activity exhibited at old age, the rat did not show another cerebral CK activity increase during senescence in either sex. However, sex differences of CK specific activity appeared in the cerebellum at all ages. From the sex-specific plateau phase at 45-60 days until 2.2 years of age, about a 41% independent increase of cerebellar CK specific activity was observed in both sexes. After puberty, the differential cerebellum-cerebrum values of CK specific activity were higher for female rats than males during youth, adulthood and senescence. The present work shows that in rat cerebrum and cerebellum, production of ATP through anaerobic transphosphorylation by the CK/PC system is sex-and age-specific, especially in the cerebellum, when glycolysis and the Krebs cycle lose capacity. As in rat heart, under physiological conditions at all ages the several cCK isoenzymes do participate in a gender-specific manner, in favor of females, in diverse functions of the different cell compartments of glial and neuronal cells with regard to their high and fluctuating energy demands not completely covered by anaerobic and aerobic glycolysis.

Aging↗
PubMed1998

Role of retinoic acid in regulation of mRNA expression of CaBP-D28k in the cerebellum of the chicken.

In contrast to vitamin D3-dependent gene expression of calbindin (CaBP-D28k) in intestine and kidney, the cerebellar mRNA expression seems independent of vitamin D3. The present study was conducted to elucidate correlation of mRNA expression of CaBP-D28k and vitamin D3 receptor (VDR) in the kidney and cerebellum of the developing chick by Northern blot analysis, localization of CaBP-D28k mRNA within the cerebellum by in situ hybridization, and effect of retinoic acid in ovo on CaBP-D28k mRNA levels. CaBP-D28k mRNA levels were low in the cerebellum until embryonic day 16 (E16) but markedly increased on E18 and reached plateau levels on E20. VDR mRNA levels were low until E16 and significantly increased on E18 but decreased on E20 and remained low on 1 and 7 days after hatching. In the mesonephros, CaBP-D28k mRNA levels were high until E16 but abruptly decreased on E18, while VDR mRNA levels remained relatively constant throughout the examined period between E10 and 20. In situ hybridization analysis clearly demonstrated CaBP-D28k mRNA signals within the Purkinje cells of the cerebellum in the embryo on E12-E18. Although 1.25 dihydroxyvitamin D3 [1.25(OH)2D3, 3 x 10(-10) M injected in ovo on E15 increased CaBP-D28k mRNA levels in the mesonephros on E16 but had no effect on those in the cerebellum. On the contrary, in ovo injection of retinoic acid (10(-10) and 10(-8) M) caused no effect on CaBP-D28k mRNA levels in the mesonephros but significantly increased those in the cerebellum. The results indicate a regulatory role of retinoic acid on mRNA expression of CaBP-D28k in the cerebellar Purkinje cells of the chicken embryo.

Animals↗
PubMed1998

Retinoid-binding proteins in the cerebellum and choroid plexus and their relationship to regionalized retinoic acid synthesis and degradation.

The expression of cellular retinoic-acid-binding protein (CRABP) and cellular retinol-binding protein (CRBP), as well as their relationship to retinoic acid (RA) synthesis and degradation were examined in the developing mouse cerebellum and choroid plexus of the fourth ventricle. The choroid plexus, which expresses the RA-synthesizing retinaldehyde dehydrogenase RALDH-2, is likely to represent a diffusion source of RA for the closely apposed cerebellum, regulating its development. We found CRBP to be expressed in the choroid plexus and, in an in-vitro assay, addition of recombinant CRBP to RALDH-2 increased RA synthesis from retinaldehyde, with the amount of increase depending on the CRBP/retinaldehyde ratio. A technique that characterizes RA-binding proteins according to their isoelectric point showed both CRABP I and CRABP II to be present in the cerebellum and P19 cells, and only CRABP II to be present in the choroid plexus. With this technique, CRABP I could also be detected in the HL60 cell line. In addition to the two known acidic RA-binding proteins CRABP I and II, the cerebellum expressed a third RA-binding protein distinguishable by its neutral isoelectric point; the same binding protein was also detected in the olfactory bulb, kidney and testes. We used the RA-binding technique to follow the rate of elimination of bound RA from the cerebellum. A systemic injection of 0.3 micromols RA into postnatal day-1 mice was almost completely removed after 8 hours. These results suggest mechanisms by which the retinoid-binding protein may regulate the equilibrium of RA synthesis and catabolism in the cerebellum and choroid plexus.

Aldehyde Oxidoreductases↗
PubMed2000

Cannabinoid withdrawal is dependent upon PKA activation in the cerebellum.

Region-specific up-regulation of the cyclic AMP pathway is considered an important molecular mechanism in the origin of the somatic manifestations of the withdrawal syndrome to known drugs of abuse. Nevertheless, the existence of a withdrawal syndrome after prolonged cannabinoid administration has long been a controversial issue. Recent studies, in different species, have shown that withdrawal to prolonged cannabinoid exposure precipitated by the cannabinoid antagonist SR141716A is characterized by physical signs underlying impairment of motor coordination. Interestingly, cannabinoid withdrawal is accompanied by an increase of adenylyl cyclase activity in the cerebellum. Here, we investigate the functional role of the cyclic AMP pathway in the cerebellum in the establishment of cannabinoid withdrawal. We show that after SR141716A precipitation of cannabinoid withdrawal, basal and calcium-calmodulin-stimulated adenylyl cyclase activities as well as active PKA in the cerebellum increase in a transient manner with a temporal profile which matches that of the somatic expression of abstinence. Selectively blocking the up-regulation of the cyclic AMP pathway in the cerebellum, by microinfusing the cyclic AMP blocker Rp-8Br-cAMPS in this region, markedly reduced both PKA activation and the somatic expression of cannabinoid withdrawal. Our results (i) directly link the behavioural manifestations of cannabinoid withdrawal with the up-regulation of the cyclic AMP pathway in the cerebellum, pointing towards common molecular adaptive mechanisms for dependence and withdrawal to most drugs of abuse; (ii) suggest a particular role for the cerebellum as a major neurobiological substrate for cannabinoid withdrawal.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1995

NMDA receptors in rat cerebellum and forebrain: subtle differences in pharmacology and modulation.

Binding of [3H]glutamate, [3H]glycine, and the glutamate antagonist [3H]CGS-19755 to NMDA-type glutamate receptors was examined in homogenates of rat forebrain and cerebellum. Most glutamate agonists had a higher affinity at the [3H]glutamate binding site of cerebellar NMDA receptors as compared with forebrain, whereas all the glutamate antagonists examined showed the reverse relationship. The [3H]glycine binding site of forebrain and cerebellar NMDA receptors showed a similar pharmacology in both brain regions. In the cerebellum, however, [3H]glycine bound to a second site with a 10-fold lower affinity and with a pharmacology that resembled that of the glycine/strychnine chloride channel. [3H]-Glutamate binding was not affected by glycine agonists or antagonists, nor was [3H]glycine binding affected by glutamate agonists in either forebrain or cerebellum. Both CGS-19755 and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, glutamate antagonists, reduced [3H]-glycine binding in cerebellum, whereas only CGS-19755 was effective in forebrain. Glycine agonists and antagonists modulated [3H]CGS-19755 binding in forebrain and cerebellum to different extents in the two brain regions. From these studies we conclude that the cerebellar NMDA receptor has a different pattern of modulation at glutamate and glycine sites and that glycine may play a more important role in the control of NMDA function in the cerebellum as compared with forebrain.

Animals↗
PubMed2003

Subunit composition and quantitative importance of GABA(A) receptor subtypes in the cerebellum of mouse and rat.

In cerebellum, 13 different GABA(A) receptor subunits are expressed. The number of different receptor subtypes formed in this tissue, their subunit composition and their quantitative importance so far has not been determined. In the present study, immunodepletion by immunoaffinity chromatography, as well as immunoprecipitation and western blot analysis was performed using 13 different subunit-specific antibodies to provide an overview on the subunit composition and abundance of GABA(A) receptor subtypes in mouse and rat cerebellum. Results obtained indicate that alpha1betaxgamma2, alpha1alpha6betaxgamma2, alpha6betaxgamma2, alpha6betaxdelta and alpha1alpha6betaxdelta are the major GABA(A) receptor subtypes present in the cerebellum. In addition, small amounts of alpha1betaxdelta receptors and a series of minor receptor subtypes containing alpha2, alpha3, alpha4, alpha5, gamma1 or gamma3 subunits are also present in the cerebellum. Whereas the abundance of alpha1alpha6betaxgamma2, alpha6betaxdelta and alpha1alpha6betaxdelta receptors is different in mouse and rat cerebellum, that of other receptors is quite similar in these tissues. Data obtained for the first time provide an overview on the GABA(A) receptor subtypes present in the cerebellum and represent the basis for further studies investigating changes in receptor expression and composition under pathological conditions.

Animals↗
PubMed1997

Cooperation of Pax2 and Pax5 in midbrain and cerebellum development.

Midbrain and cerebellum development depends on an organizing center that is located at the midbrain-hindbrain junction of the vertebrate embryo. Expression of the two closely related transcription factors Pax2 and Pax5 overlaps spatially and temporally in this region of the developing central nervous system. To study a possible interaction of these transcription factors in midbrain and cerebellum patterning, we have generated Pax5, Krd double mutant mice. The transgene-induced Krd mutation corresponds to an approximately 7-centimorgan chromosome 19 deletion that eliminates the entire Pax2 locus. The heterozygous Krd mutation deleting one Pax2 allele had no effect on midbrain and cerebellum development. Moreover, only minor developmental defects were previously observed at the midline of the inferior colliculus and anterior cerebellum in mice that were homozygous for a targeted Pax5 mutation. Similar morphological alterations were observed in 80% of all compound heterozygous Pax5 (+/-) Krd (+/-) mice. However, in the remaining 20% of compound heterozygotes, the inferior colliculi were missing, and the vermis of the cerebellum was severely disrupted due to the failure of the cerebellar primordia to fuse at the midline. Inactivation of the second Pax5 allele in Pax5 (-/-) Krd (+/-) mice resulted in complete loss of the posterior midbrain and cerebellum, as the tissue originating from the midbrain-hindbrain boundary region was deleted in the embryo as early as day 9.5. On the basis of these data, we propose that the cooperation of Pax2 and Pax5 is essential for normal functioning of the organizing center at the midbrain-hindbrain junction.

Animals↗
PubMed2003

Brain metabolism in the cerebellum and visual cortex correlates with neuropsychological testing in patients with Alzheimer's disease.

This study was designed to measure glucose metabolic deficits in areas not typically recognized as abnormal on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scans in patients with Alzheimer's disease (AD), and to correlate such findings with subtle neuropsychological impairment. FDG-PET scans on 38 AD patients with no clinical evidence of visual, spatial or motor deficits were acquired on the PET HEAD scanner 40 min following the intravenous administration of 115 microCi.kg-1 of FDG. All FDG-PET scans were analysed blindly using a region of interest (ROI) template with regions for the primary visual cortex (PVC), secondary visual cortex (SVC) and cerebellum. Counts from the ROIs of these regions were normalized to whole brain activity and the results were compared with psychometric and neuropsychological measures. A number of significant correlations were found between these structures and various neuropsychological measures (P<0.05). Specifically, there were significant correlations between clock drawing and the cerebellum activity; memory and activity in the PVC, SVC and cerebellum; social score and activity in the PVC and left cerebellum; judgement and activity in the right SVC and right PVC; and the overall Mini-Mental State Examination and activity in the PVC, SVC and cerebellum. The results of this study suggest that metabolism in areas not typically recognized as abnormal on FDG-PET scans in AD, such as the PVC, SVC and cerebellum, is correlated with deficits in neuropsychological function. This may have important clinical and pathophysiological implications in the study of AD and other illnesses of dementia.

Aged↗