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PubMed1997

GABAA receptor subunit expression changes in the rat cerebellum and cerebral cortex during aging.

Significant aging-related decreased expression of various GABAAR subunit mRNAs (alpha 1, gamma 2, beta 2, beta 3 and sigma) was found in both cerebellum and cerebral cortex using quantitative dot blot and in situ hybridization techniques. Contrary to the other subunits, the alpha 6 mRNA expression was significantly increased in the aged cerebellum. Parallel age-related changes in protein expression for gamma 2 and beta 2/3 (decrease) and alpha 6 (increase) were revealed in cerebellum by quantitative immunocytochemistry. However, no significant changes in alpha 1 protein expression nor in the number or affinity of [3H]zolpidem binding sites were detected in cerebellum even though alpha 1 mRNA expression was significantly decreased in the aged rat. Age-related increased expression of alpha 6 mRNA and protein in the cerebellum was accompanied by no significant changes in the number of diazepam-insensitive [3H]Ro15-4513 binding sites. In the cerebral cortex, no changes in the protein expression of the main GABAA receptor subunits (alpha 1, gamma 2 and beta 2/3) were observed which contrasted with the age-related decreased expression of the corresponding mRNAs. No significant changes in the number or affinity of [3H]zolpidem binding sites were observed in the cerebral cortex. Thus, age-related changes in the mRNA expression of a particular subunit does not necessarily lead to similar changes in protein or assembly into mature GABAA receptors. The results reveal the existence of complex regulatory mechanisms of GABAA receptor expression, at the transcriptional, translational and post-translational and/or assembly levels, which vary with the subunit and brain area.

Aging↗
PubMed1998

Cloning of PCPTP1-Ce encoding protein tyrosine phosphatase from the rat cerebellum and its restricted expression in Purkinje cells.

Recently, cDNAs encoding brain-specific transmembrane-type protein tyrosine phosphatases (PTPs) with single catalytic domain have been cloned. These include PC12-PTP, PCPTP1, PTPBR7, and PTP-SL, whose cytoplasmic domains had high similarity to STEP, a brain-specific nontransmembrane-type PTP. Based on the high similarity and expression pattern, PCPTP1 seems to be identical with PC12-PTP1 and to be the rat homologue of murine PTPBR7. Here, we report the molecular cloning and expression profile of PCPTP1-Ce, a variant of PCPTP1. Both PCPTP1 mRNA and PCPTP1-Ce mRNA seem to be derived from a single common region gene. Nucleotide and deduced amino acid sequence comparison between PCPTP1-Ce and PCPTP1 revealed that the predicted protein product of PCPTP1-Ce is identical with that translated from the third initiation methionine of the longest ORF of PCPTP1, and that these two clones differ in the 5'-untranslated sequences. Northern blot analyses with specific probes for PCPTP1 and PCPTP1-Ce confirmed our previous observation that PCPTP1-Ce mRNA was almost exclusively expressed in the cerebellum, whereas PCPTP1 was widely expressed in various brain regions dissected including cerebellum. In situ hybridization study demonstrated that PCPTP1-Ce mRNA was exclusively expressed in Purkinje cells of the cerebellum. In contrast, PCPTP1 mRNA was predominantly expressed in granule cells and less in Purkinje cells. Moreover, immunohistochemical analysis using an affinity-purified polyclonal antibody raised against the cytoplasmic region of PCPTP1/PCPTP1-Ce demonstrated that Purkinje cells were strongly immunostained, whereas granule cells were stained only faintly in the cerebellum. These observations clearly demonstrated that PCPTP1-Ce mRNA and its protein products are expressed in Purkinje cells and suggest that PCPTP1-Ce may play an important role in Purkinje cell function in the rat cerebellum.

Animals↗
PubMed2000

Expression of estrogen receptor-beta protein and mRNA in the cerebellum of the rat.

Estrogen has been shown to play a modulatory role in cerebellar neuronal signaling. Recent reports have also shown that estrogen receptor beta (ER-beta) mRNA is expressed in cerebellum. The purpose of the present study was to identify and map ER-beta protein expression, and to determine the identity of the major splice variants of ER-beta mRNA in the cerebellum. Polyclonal antibodies raised against the NH(3)- and COOH-termini of rat ER-beta were used for immunohistochemistry. Mapping of ER-beta immunoreactivity was compared with the distribution of ER-beta mRNA using in situ hybridization. We also determined, using RT-PCR, whether the ER-beta mRNA was variably spliced in cerebellum. Our results show that in all cases the distribution of ER-beta protein was identical to the distribution of ER-beta mRNA. Both Purkinje cells and scattered cells in the granule cell layer, perhaps golgi cells, robustly expressed ER-beta. Reverse transcription-polymerase chain reaction analysis showed that three splice variants in addition to wild type ER-beta are expressed in rat cerebellum. However, wild type ER-beta was the predominant form. These observations provide anatomical evidence that neurons in the cerebellum express ER-beta and thus may be targets of estrogen action.

Animals↗
PubMed2002

Immunocytochemical localization of neuronal calcium sensor-1 in the hippocampus and cerebellum of the mouse, with special reference to presynaptic terminals.

Neuronal calcium sensor-1 (NCS-1) is a member of the EF-hand calcium-binding protein superfamily, which is considered to modulate synaptic transmission and plasticity. In this work, we first examined the distribution patterns of NCS-1 in the hippocampus and cerebellum. The intense NCS-1-immunoreactive (IR) elements in the hippocampus were restricted to dendritic layers, while those in the cerebellum occurred in both dendritic and cellular layers. Then, we examined the exact localization of NCS-1 using immunofluorescent double labeling for NCS-1 and synaptophysin, a marker of presynaptic terminals. In the hippocampus, the mossy fiber systems (terminals and bundles) exhibited intense NCS-1 immunoreactivity. On the other hand, the presumed principal cell dendrites were also NCS-1-IR in the stratum lacunosum-moleculare of Ammon's horn and molecular layer of the dentate gyrus, where NCS-1-IR elements and synaptophysin-IR presynaptic terminals showed characteristic complementary distribution patterns. In the cerebellum, some of the basket cell axon terminals surrounding the somata of Purkinje cells exhibited NCS-1 immunoreactivity, while the pinceau showed consistent labeling for NCS-1. Higher magnification observations revealed that the NCS-1-IR presumed granule cell dendrites and synaptophysin-IR mossy fiber terminals in the glomeruli of the cerebellum showed characteristic complementary distribution patterns. Furthermore, we estimated quantitatively the relative amount of NCS-1 in the presynaptic terminals in individual layers, and confirmed that the mossy fiber terminals in the hippocampus contained comparatively high amounts of NCS-1. These results showed the diverse localization of NCS-1 in pre- and/or postsynaptic elements of the hippocampus and cerebellum, and suggest potential roles in specific synaptic transmission.

Animals↗
PubMed1998

Expression and heteromeric interactions of non-N-methyl-D-aspartate glutamate receptor subunits in the developing and adult cerebellum.

The localization and expression of ionotropic non-N-methyl-D-aspartate glutamate receptors (GluR) were investigated in the developing and adult rat cerebellum using subunit-specific polyclonal antibodies for immunocytochemical, immunoblot and immunoprecipitation studies. In P7 animals, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor immunoreactivity was detected in all layers of the cerebellar cortex with the exception of the external granule cell layer. Antibodies against the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunits GluR1 and GluR4 gave strong immunoreactive staining of Bergmann glia in both young and adult animals, and both antibodies showed prominent staining of the molecular layer in the adult cerebellum. Dense immunoreactive staining of Purkinje cell somata and dendrites was obtained with anti-GluR2/3/4c in both the developing and adult cerebellum. Whereas each of the three alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antibodies stained the internal, but not the external, granule cell layer, immunostaining for the kainate-type subunits GluR6/7 and KA2 was detected in both the external and internal granule cell layers. as well as in the molecular layer in both P7 and adult cerebellum. Immunoblot analysis of total cerebellar protein indicated that the level of GluR4 expression increased 15-fold from P1 to P18, whereas the expression of the KA2 subunit protein was nine-fold lower in adult cerebellum than it was at P1. The expression of GluR1 increased moderately (two-fold) from P1 to adult. Subunit interactions between GluR1 and GluR4, as well as between GluR6/7 and KA2, were demonstrated in immunoprecipitation experiments; and the GluR4 and KA2 subunits appear to be present exclusively in heteromeric assemblies with GluR1 and GluR6/7, respectively. The results show that the various alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate- and kainate-type subunits are differentially expressed during cerebellar development and further define the possible subunit composition of non-N-methyl-D-aspartate receptors in the major cerebellar cell types.

Animals↗
PubMed2002

Cerebellum segmentation employing texture properties and knowledge based image processing: applied to normal adult controls and patients.

A semi-automated method is described for segmenting the cerebellum from T(1)-weighted 3-dimensional magnetic resonance imaging scans of adult controls and patients. The method relies on prior knowledge involving a user-defined template as a guide to aid the segmentation of the cerebellum. As the gray and white matter intensity distribution in the cerebellum has a complex pattern, texture information that identified the "graininess" was employed to capture the intensity distribution of voxels. The textural information was used to group voxels in a small circular structuring element as belonging to the cerebellum region. The cerebella from scans of 15 of the 20 subjects were segmented both manually and using the semi-automated procedure; the results were strongly correlated (r = 0.985, n = 15, p < 0.0001), and the volumes obtained from the two methods differed by 2.3%. The cerebellar volumes in 10 normal subjects and 10 age- and sex-matched patients with a neuropsychiatric disorder (schizophrenia) did not differ significantly (p = 0.18). The whole cerebellum was segmented in approximately 30 min using the semi-automated procedure. The method described is robust, easy-to-use, fairly fast and gives objective measurements.

Cerebellum↗
PubMed2003

L-2-hydroxyglutaric acid inhibits mitochondrial creatine kinase activity from cerebellum of developing rats.

L-2-Hydroxyglutaric acid (LGA) is the biochemical hallmark of patients affected by the neurometabolic disorder known as L-2-hydroxyglutaric aciduria (LHGA). Although this disorder is predominantly characterized by severe neurological findings and pronounced cerebellum atrophy, the neurotoxic mechanisms of brain injury are virtually unknown. In the present study, we investigated the effect of LGA, at 0.25-5mM concentrations, on total creatine kinase (tCK) activity from cerebellum, cerebral cortex, cardiac muscle and skeletal muscle homogenates of 30-day-old Wistar rats. CK activity was measured also in the cytosolic (Cy-CK) and mitochondrial (Mi-CK) fractions from cerebellum. We verified that tCK activity was significantly inhibited by LGA in the cerebellum, but not in cerebral cortex, cardiac muscle and skeletal muscle. Furthermore, CK activity from the mitochondrial fraction was inhibited by LGA, whereas that from the cytosolic fraction of cerebellum was not affected by the acid. Kinetic studies revealed that the inhibitory effect of LGA on Mi-CK was non-competitive in relation to phosphocreatine. Finally, we verified that the inhibitory effect of LGA on tCK was fully prevented by pre-incubation of the homogenates with reduced glutathione (GSH), suggesting that this inhibition is possibly mediated by oxidation of essential thiol groups of the enzyme. Considering the importance of creatine kinase activity for energy homeostasis, our results suggest that the selective inhibition of this enzyme activity by increased levels of LGA could be possibly related to the cerebellar degeneration characteristically found in patients affected by L-2-hydroxyglutaric aciduria.

Animals↗
PubMed2000

Localization of gp130 in the developing and adult mouse cerebellum.

Interleukin-6 (IL-6) type cytokines show functional redundancy in the immune, hematopoietic, and nervous system, which is believed to result from sharing of the signal transducing receptor gp130. IL-6 type cytokines and their binding receptors have been localized in the adult cerebellum. However, the cellular localization and developmental regulation of gp130 in the cerebellum have not been determined. In the present study the expression pattern of gp130 in the developing and adult mouse cerebellum was investigated. At embryonic day (E)15 and E17, gp130 immunoreactivity is present primarily in fiber bundles that course from the brainstem to the cerebellum. At postnatal day (P)0, gp130 immunoreactivity first appears in the Purkinje cell layer, external granule cell layer, and cerebellar nuclei. As Purkinje cells differentiate, gp130 immunoreactivity progressively extends from the cell body along their developing dendritic arbor. All Purkinje cells show intense gp130 immunoreactivity in their cell bodies by P7. In contrast the gp130 immunoreactivity detected in fiber bundles at E15 and E17 is downregulated postnatally, and cannot be detected after P7. Granule cells show gp130 immunoreactivity at P0 in the external granule cell layer and subsequently in the internal granule cell layer. Astrocytes in the white matter express gp130 at P0, and show intense gp130 immunoreactivity between P7 and P14. As the cerebellum matures gp130 immunoreactivity in the white matter decreases. The present description of the differential spatial and temporal distribution of gp130 provides an initial step in defining specific cellular populations that are potential targets of IL-6 type cytokines during cerebellar ontogeny.

Animals↗
PubMed1996

The temporal and spatial development of corticotropin-releasing factor (CRF) binding sites and CRF afferents in the opossum cerebellum.

The intent of this study is to determine the developmental timecourse of the appearance and distribution of corticotropin releasing factor (CRF) binding sites within the developing opossum cerebellum, and to correlate this with the temporal and spatial distribution of CRF-labeled axons. 125I-labeled ovine CRF was used to identify the distribution and temporal expression of CRF binding sites in the opossum cerebellum. By PD8, binding sites are evident over cells in the external granular layer, as well as the subjacent immature Purkinje cell layer, but not over the ventricular layer or the intermediate zone. At PD 8, the intermediate zone, located between the ventricular and immature Purkinje cell layers, contains migrating nuclear, Golgi and Purkinje cells. By PD12, binding sites are present over all layers of the immature cerebellum (the external granular layer, the multitiered Purkinje cell layer, and the intermediate zone of migrating cells), except the ventricular layer. The adult distribution of CRF binding sites is evident by PD30-38 which includes the molecular, Purkinje and internal granule cell layers. The present results provide the first account of the ontogeny of CRF binding sites in the developing cerebellum. The early expression and distribution of CRF receptors, when correlated with the temporal expression and distribution of the peptide, provide additional evidence to support our working hypothesis that CRF functions as a regulator of developmental events which is distinct from its proposed function as a neuromodulator in the mature cerebellum.

Afferent Pathways↗
PubMed2000

Tyrosine hydroxylase- and dopamine transporter-immunoreactive axons in the primate cerebellum. Evidence for a lobular- and laminar-specific dopamine innervation.

The cerebellum seems to play a critical role in many motor and cognitive functions, including those that are disturbed in schizophrenia. Although dopamine is known to influence the motor or cognitive functions mediated by other brain regions and to play a role in the pathophysiology of schizophrenia, the cerebellum has not been thought to be a target of dopamine-containing axons. However, given recent reports of dopamine receptors in the cerebellum, we sought to determine whether axons immunoreactive for the proteins involved in dopamine synthesis and reuptake are present in the cerebellum of macaque monkeys. We found that axons immunoreactive for the dopamine membrane transporter, a specific marker of dopamine axons, were present in high density, but only in certain lobules of the cerebellar vermis. In addition, these axons were found principally in the granule cell layer, where they densely arborized immediately subjacent to the Purkinje cells. Similarly, axons labeled for tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, were also present in high density in the granule cell layer of the same lobules of the vermis. In contrast, axons immunoreactive for dopamine beta-hydroxylase, a marker of noradrenergic axons, exhibited a different and more widespread pattern of innervation. These findings are consistent with a dopamine innervation of the primate cerebellum that is both lobular- and laminar-specific, and they suggest that dopamine may play a role in certain cerebellar functions.

Animals↗
PubMed1998

Single-voxel proton magnetic resonance spectroscopy of the pons and cerebellum in patients with schizophrenia: a preliminary study.

Magnetic resonance spectroscopy (MRS) is a non-invasive functional imaging technique that can measure various brain tissue metabolites such as N-acetylaspartate (NAA), choline (Cho), creatine-phosphocreatine (Cr), myo-inositol (mI) and other metabolites. Morphological studies have indicated the pons and cerebellum as possible sites of abnormal functioning in schizophrenic patients. This study examines schizophrenic patients for the presence of abnormalities in proton MRS (1H-MRS) measured metabolites in two regions of the posterior fossa. Twelve schizophrenic patients and eight non-schizophrenic control subjects were studied by measuring the ratios of NAA/Cr, Cho/Cr and mI/Cr from 1H-spectra obtained from the pons and right or left cerebellum using an integrated MRI/MRS protocol. Spectra were obtained from a voxel in the pons and voxels from the left and/or right lateral cerebellum. Data were analyzed in the absorption mode and fitted to Lorentzian lineshapes using a Marquart algorithm. Significantly lower NAA/Cr ratios were found in the pons of schizophrenic patients than in the control subjects, but not in the cerebellum. This study is the first to measure brain tissue metabolites using 1H-MRS in the pons and cerebellum of schizophrenic patients. Significant alterations of 1H-MRS metabolites may suggest the involvement of the posterior fossa as a part of the pathological substrate underlying schizophrenia.

Adult↗
PubMed2002

rTMS over the cerebellum can increase corticospinal excitability through a spinal mechanism involving activation of peripheral nerve fibres.

OBJECTIVES: Single-pulse transcranial magnetic stimulation (TMS) over the cerebellum affects corticospinal excitability by a cerebellar and a peripheral mechanism. We have investigated whether any of the long-lasting effects of repetitive TMS (rTMS) over cerebellum can also be attributed to peripheral effects. METHODS: Five hundred conditioning stimuli at 1 Hz were given over either the right cerebellum using a double-cone coil, or over the right posterior neck using a figure-8-coil. Corticospinal excitability was assessed by measuring the amplitude of motor evoked potentials (MEPs) evoked in the right and left hand and forearm muscles. Hoffman reflexes (H-reflex) were also obtained in the right flexor carpi radialis muscle. RESULTS: rTMS over either the right cerebellum or the right posterior neck significantly facilitated MEPs in hand and forearm muscles in the right but not in the left arm (n=8) for up to 30 min after the end of the train. rTMS (1 Hz) of the right neck area increased the amplitude of the H-reflex (n=5). CONCLUSIONS: Much of the persisting effects of rTMS over the cerebellum on corticospinal excitability appear to be mediated through stimulation of peripheral rather than central structures. Moreover, the results show that rTMS over peripheral areas can cause long-lasting changes in spinal reflexes.

Adult↗
PubMed2003

Muscle afferent inputs from the hand activate human cerebellum sequentially through parallel and climbing fiber systems.

OBJECTIVE: Spatio-temporal response characteristics of the human cerebellum to median nerve stimulation (MNS) were studied with the use of a whole-head magnetoencephalographic (MEG) system covering the cerebellum and upper cervical spine. METHODS: Neuromagnetic responses from the cerebellum were recorded following electric stimulation of the right median nerve in 12 subjects. In 6 out of 12 subjects, the responses to the left median nerve and to the right index or middle finger stimulation were also recorded. RESULTS: The medial part of the cerebellum (spinocerebellum) was activated by MNS. In contrast, there were no responses from the cerebellum to the finger stimulation, suggesting that muscle afferent inputs are the source of cerebellar activation for MNS. The cerebellar responses consisted of 3 or 4 components of alternating polarity within 90 ms post-stimulus: the current direction for the first component was from the depth to the surface of the anterior lobe. CONCLUSIONS: From the timing and current direction, we speculate that the 4 components reflect, respectively, (1) excitatory postsynaptic potentials (EPSPs) of granule cells, (2) Purkinje cell EPSPs at the distal dendrites driven by parallel fibers, (3) Purkinje cell EPSPs at the soma and the proximal dendrites mediated by climbing fibers and (4) second Purkinje cell EPSPs at the distal dendrites driven by parallel fibers. SIGNIFICANCE: We first visualized serial activation of the human spinocerebellum following MNS noninvasively with MEG.

Adult↗
PubMed1991

Brain calbindin-D28k and an Mr 29,000 calcium binding protein in cerebellum are different but related proteins: evidence obtained from sequence analysis by tandem mass spectrometry.

A calcium binding protein of Mr 29,000 which cross-reacts with antibodies raised against chick calbindin-D28k was previously reported to be present in rat cerebellum [Pochet, R., Parmentier, M., Lawson, D. E. M., & Pasteels, J. L. (1985) Brain Res. 345, 251-254]. It was suggested that the Mr 29,000 protein represents another form of calbindin-D28k. In our laboratory we were able to identify Mr 28,000 and 29,000 proteins in rat, human, and chick cerebellum by their ability to bind 45Ca in a 45Ca blot assay. Two calcium binding proteins of Mr 27,680 and 29,450 were isolated from rat cerebelli by the use of gel permeation chromatography and preparative gel electrophoresis. After reverse-phase high-performance liquid chromatography (HPLC) the proteins were sequenced. Sequence analysis by tandem mass spectrometry indicated only 52% identity between the rat cerebellar Mr 28,000 and 29,000 proteins. Thus they are not different forms of the same protein, as previously suggested. Eighty-nine percent identity was observed between the rate cerebellar Mr 29,000 protein and chick calretinin [Rogers, J. H. (1987) J. Cell Biol. 105, 1343-1353]. The difference in identity between the rat cerebellar Mr 29,000 protein and chick calretinin may be due to species differences, and thus this protein is most likely rat calretinin. However, barely detectable levels of mRNA and weak immunoreactivity have been reported for calretinin in cerebellum. Since we found the Mr 29,000 calcium binding protein to be an abundant protein in rat cerebellum, these results suggest either posttranscriptional regulation of calretinin in cerebellum or species differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1989

Reappraising the cerebellum: what does the hindbrain contribute to the forebrain?

Although the cerebellum has traditionally been regarded as a motor mechanism, recent behavioral evidence indicates that the human cerebellum is involved in a wider range of functions: in learning, in planning, in judging time, in some emotional and cognitive disorders such as autism, and in some normal mental activities such as the cognitive processing of words. This evidence suggests that the traditional view of cerebellar function now needs to be reassessed and enlarged to include nonmotor as well as motor functions in the human brain. Whereas the cerebellar connections to frontal motor areas enable the cerebellum to improve motor skills, cerebellar connections to adjacent association areas of the prefrontal cortex can enable the cerebellum to improve mental skills, and cerebellar connections to Broca's area can enable the cerebellum to improve language skills.

Animals↗
PubMed1999

GABA(B) receptor isoforms GBR1a and GBR1b, appear to be associated with pre- and post-synaptic elements respectively in rat and human cerebellum.

1. Metabotropic gamma-aminobutyric acid (GABA) receptors, GABA(B), are coupled through G-proteins to K+ and Ca2+ channels in neuronal membranes. Cloning of the GABAB receptor has not uncovered receptor subtypes, but demonstrated two isoforms, designated GBR1a and GBR1b, which differ in their N terminal regions. In the rodent cerebellum GABA(B) receptors are localized to a greater extent in the molecular layer, and are reported to exist on granule cell parallel fibre terminals and Purkinje cell (PC) dendrites, which may represent pre- and post-synaptic receptors. 2. The objective of this study was to localize the mRNA splice variants, GBR1a and GBR1b for GABA(B) receptors in rat cerebellum, for comparison with the localization in human cerebellum using in situ hybridization. 3. Receptor autoradiography was performed utilizing [3H]-CGP62349 to localize GABA(B) receptors in rat and human cerebellum. Radioactively labelled oligonucleotide probes were used to localize GBR1a and GBR1b, and by dipping slides in photographic emulsion, silver grain images were obtained for quantification at the cellular level. 4. Binding of 0.5 nM [3H]-CGP62349 demonstrated significantly higher binding to GABA(B) receptors in the molecular layer than the granule cell (GC) layer of rat cerebellum (molecular layer binding 200+/-11% of GC layer; P<0.0001). GBR1a mRNA expression was found to be predominantly in the GC layer (PC layer grains 6+/-6% of GC layer grains; P<0.05), and GBR1b expression predominantly in PCs (PC layer grains 818+/-14% of GC layer grains; P<0.0001). 5. The differential distribution of GBR1a and GBR1b mRNA splice variants for GABA(B) receptors suggests a possible association of GBR1a and GBR1b with pre- and post-synaptic elements respectively.

Aged↗
PubMed1999

Modulation of mPer1 gene expression by anxiolytic drugs in mouse cerebellum.

1. The mPer1 and mPer2 genes are putative mouse clock genes that regulate circadian oscillator present in the suprachiasmatic nucleus (SCN) neuron. While they are also expressed in the granular cell layer in the cerebellum, their function is unknown. In a first step to verify the physiological roles of mPer1 and mPer2 genes in the cerebellum, we examined the effects of benzodiazepines on the expression of the mPer1 and mPer2 genes. 2. mPer2 mRNA expression was higher at ZT16 than ZT4 in the mouse cerebellum. 3. High-dose administration of diazepam (10 mg kg-1) or triazolam (1 mg kg-1) reduced mPer1 mRNA level 1 h after treatment in the cerebellum. 4. Reduced expression of mPer1 by diazepam treatment was transient. No difference of mPer1 mRNA level between diazepam (10 mg kg-1)- and vehicle-treated group was observed 6 h after treatment. 5. Administration of high doses of tandospirone (30 mg kg-1), a non-benzodiazepine anxiolytic also reduced mPer1 mRNA expression 1 h after treatment. 6. Administration of high doses of clozapine (5 mg kg-1) or haloperidol (1 mg kg-1) impaired the rota-rod performance without affecting on mPer1 mRNA level. 7. Diazepam and tandospirone inhibited the expression of mPer1 mRNA in the primary cultured cerebellum granule cells. 8. Transient reductions of mPer1 mRNA levels by various benzodiazepines and tandospirone is associated with impairment of coordinated movement, such as rota-rod performance and equilibrium.

Animals↗
PubMed2001

Deficient long-term synaptic depression in the rostral cerebellum correlated with impaired motor learning in phospholipase C beta4 mutant mice.

Long-term depression (LTD) at parallel fibre-Purkinje cell synapse of the cerebellum is thought to be a cellular substrate for motor learning. LTD requires activation of metabotropic glutamate receptor subtype 1 (mGluR1) and its downstream signalling pathways, which invariably involves phospholipase Cbetas (PLCbetas). PLCbetas consist of four isoforms (PLCbeta1-4) among which PLCbeta4 is the major isoform in most Purkinje cells in the rostral cerebellum (lobule 1 to the rostral half of lobule 6). We studied mutant mice deficient in PLCbeta4, and found that LTD was deficient in the rostral but not in the caudal cerebellum of the mutant. Basic properties of parallel fibre-Purkinje cell synapses and voltage-gated Ca2+ channel currents appeared normal. The mGluR1-mediated Ca2+ release induced by repetitive parallel fibre stimulation was absent in the rostral cerebellum of the mutant, suggesting that their LTD lesion was due to the defect in the mGluR1-mediated signalling in Purkinje cells. Importantly, the eyeblink conditioning, a simple form of discrete motor learning, was severely impaired in PLCbeta4 mutant mice. Wild-type mice developed the conditioned eyeblink response, when pairs of the conditioned stimulus (tone) and the unconditioned stimulus (periorbital shock) were repeatedly applied. In contrast, PLCbeta4 mutant mice could not learn the association between the conditioned and unconditioned stimuli, although their behavioural responses to the tone or to the periorbital shock appeared normal. These results strongly suggest that PLCbeta4 is essential for LTD in the rostral cerebellum, which may be required for the acuisition of the conditioned eyeblink response.

Animals↗