Caudal Cerebellum Research Articles

Neuroradiological characteristics of hydrocephalus due to idiopathic extraventricular CSF pathways obstruction

The development of research on CSF flow disorders made it possible initially to divide hydrocephalus into «communicating» and «non-communicating», and subsequently to distinguish the concepts of «intraventricular» and «extraventricular» obstruction. Improvement of radiological imaging technologies has allowed determining the exact level of CSF obstruction. In some cases, CSF flow disorders combine signs of different forms of hydrocephalus. Their correct classification allows selecting the type of surgical treatment, which reduces the rate of complications and patient»s dependence on the doctor. Purpose of the research: To study the radiological signs of hydrocephalus in idiopathic obstruction at the level of the posterior cranial fossa cisterns. Materials and methods. This study included adult patients (18 years old and over) whose disease was idiopathic in nature. From 2007 to 2020, 289 patients diagnosed with idiopathic hydrocephalus were treated at the N. N. Burdenko National Medical Research Center of Neurosurgery. Of these, 65 patients (18.7 %) had clinical and radiological signs of extraventricular obstruction. The male to female ratio was 25 and 40 (38.5 % and 61.5 %), respectively. A variety of radiological signs were assessed and their origin and occurrence in various forms of idiopathic hydrocephalus were determined. Results. FOHR was the highest (compared with other forms of idiopathic hydrocephalus (mean 0.52)). Other ventricular indices were also high. None of them correlated with the patient»s condition. Ventral dislocation of the premamillary membrane was detected in 89.2 %. Turkish saddle was of normal size in 51 (78.4 %) patients, while its enlargement was found in 13 (20 %) patients. A change in the periventricular signal was noted in 18.4 %. Aqueduct and IV ventricle outlets were patent in all cases as evidenced by CSF pulsation artifacts in T2 3D CUBE. The cerebral aqueduct was dilated in 63 (96.9 %) patients. Enlargement of the cisterna magna associated with hypotrophy of the caudal cerebellum was noted in 90.7 %, and this sign was significant for extraventricular cisternal obstruction (p <0.001). In addition to the T2 mode, the presence of sagittal sections in cisternography modes (FIESTA or CISS) was a prerequisite. By means of these modes, the ventral dislocation of the premamillary membrane was more clearly visualized, the presence of obstacles to the CSF flow in the cerebral aqueduct was excluded, and, most importantly, it was possible to determine the presence of additional membranes in the subarachnoid spaces between the ventral surface of the brain stem and the clivus. These were found in 100 % of the patients, which was also a significant pathognomonic sign (p < 0.001). Conclusion. The MRI picture of hydrocephalus with obstruction at the level of the posterior cranial fossa cisterns has specific signs. It combines the signs of other forms of hydrocephalus, chronic disease in combination with symptoms of the CSF pathways obstruction. It can be classified into a separate form and both endoscopic and shunt surgery can be used for treatment.

Surgical Outcomes of Adult Chiari Malformation Type 1: Experience at a Tertiary Institute.

BackgroundChiari type I malformation (CM1) is a herniation of the caudal cerebellum and/or medulla oblongata into the upper spinal canal, occurring in pediatric and adult populations. We aimed to analyze the surgical outcomes of adult patients with CM1 consecutively treated with a posterior fossa decompression and duraplasty (PFDD) in a tertiary institution.Patients and methodsWe retrospectively reviewed the medical charts of 45 adult patients with CM1 who underwent PFDD at the Neurosurgery Department of our institution between January 2012 and December 2017. Radiological evaluation was based on pre- and postoperative syrinx/cord ratio, syrinx length, and regression of the ectopic cerebellar tonsils on coronal and sagittal magnetic resonance imaging (MRI) images, and clinical assessment of the patients was performed with the Chicago Chiari Outcome Scale (CCOS).ResultsOf the 45 patients included in the study, 25 (four men, 21 women) were diagnosed with symptomatic CM1 with an age average of 36.6±11.4 (18-66) years. Headache was the most common symptom (72.0%), while pinprick losses were prevalent in 13 (52.0%) patients. The mean postoperative CCOS score was 14.7±2.0 (8-16). Symptoms improved in 20 patients (80.0%) at the last follow-up. The mean regression in ectopic tonsils on midsagittal and coronal images were 9.1±1.8 (range: 0-16.5) mm and 8.3±1.2 (0-12.0) mm, respectively (p<0.05). The syrinxes had regressed completely or significantly in 7 (87.5%) of eight patients with syrinx.ConclusionOur findings showed that PFDD is sufficient to relieve most of the major symptoms and resolve the syrinx cavity without additional surgical interventions. The CCOS keeps its measurability of assessment of the clinical outcomes. A reliable radiological evaluation should be performed on midsagittal and coronal MRI images.

Clinical and radiological evaluation of treated Chiari I adult patients: retrospective study from two neurosurgical centers.

Chiari malformation type I (CM1) is a common neurosurgical disorder. It often causes debilitation in the affected patients. CM1 is a herniation of the caudal cerebellum into the spinal canal. This study aimed to evaluate the clinical and radiological outcomes of posterior fossa decompression and duraplasty (PFDD) in treated CM1 patients. In retrospective design, we reviewed the medical records of diagnosed patients with CM1 at two neurosurgical centers spanning 8years from 2010 to 2017. We selected all CM1 patients who underwent PFDD surgery (n = 72) as the core sample for this study. We used the Chicago Chiari Outcome Scale (CCOS) to evaluate clinical outcomes. Pre- and postoperatively, we assessed the syrinx/cord ratio, the syrinx length, and the improvement of aqueductal stroke volume (ASV) on CSF flow MRIs. The mean value of CCOS was 14.1 ± 2.1. On midsagittal MRIs, the mean regression in ectopia tonsils was 9.4 ± 1.9mm (i.e., mean pre- and postoperative tonsil herniation was 13.1 ± 3.1mm and 4.0 ± 1.6mm, respectively; p < 0.001). On coronal MRIs, the mean regression in ectopia tonsils was 8.4 ± 1.5mm (i.e., mean pre- and postoperative tonsil herniation was 13.9 ± 2.4mm and 5.8 ± 1.0mm, respectively; p < 0.001). A strong positive correlation was observed between clinical improvement and the increase in ASV values. CSF flow MRIs can help in the surgical decision and follow-up of CM1 patients. ASV ≤ 12μl is a significant predictor for surgical intervention. Full clinical and radiological evaluation utilizing CSF flow MRI are essential. Most syrinx cavities have regressed following PFDD.

Immunohistochemical evaluation of natural cases of encephalitic listeriosis in sheep

ABSTRACTListeriosis is an important public health problem in the world. It can cause abortion, encephalitis, septicemia, conjunctivitis and mastitis in ruminants. The development of central nervous system lesions is not fully understood in encephalitic listeriosis. We performed a retrospective analysis of 15 sheep with encephalitic listeriosis. Hyperemia and opacification of the meninges were common necropsy findings. Lesions generally were localized in the caudal part of the brain including the pons, medulla oblongata, thalamus and cerebellum. Microabscesses usually were found in the caudal brain and cerebellum, while perivascular infiltrates were found most often in other parts of the brain. Evidence of Listeria monocytogenes was detected immunohistochemically in the medulla oblongata, pons, thalamus and cerebellum. Prominent reactions for glial fibrillary acidic protein (GFAP), S100 protein, N-methyl-D-aspartate receptor-1 (NMDAR1) and inducible co-stimulatory protein (ICOS) were detected in the caudal brain, which indicates that these proteins may play roles in the pathogenesis of encephalitic listeriosis.

Paradoxical Vestibular Syndrome Secondary to Temporal Bone Osteomyelitis and Chronic Otitis Interna in a Guinea Pig (Cavia porcellus)

A 3-year-old female intact guinea pig (Cavia porcellus) was presented for torticollis and ocular discharge. On examination, the guinea pig had a left head tilt with corneal ulceration and absent palpebral response of the right eye. Computed tomography showed a soft tissue attenuating mass with multifocal mineralization compressing the caudal cerebellum with moderate lysis of the calvarium. On recheck, the disease had progressed to include ataxia and proprioceptive deficits. Systemic antibiotic therapy was initiated but the guinea pig only exhibited a marginal treatment response. Due to poor quality of life, the guinea pig was euthanized. A necropsy was performed and a bony lesion was found within the skull compressing the right cerebellum and temporal lobe. Histopathology revealed suppurative osteomyelitis consistent with severe chronic bacterial otitis interna. Vestibular signs in small exotic companion mammals are a common sequela to otitis interna, often noted ipsilateral to an affected inner ear, however, in this case rare paradoxical vestibular signs were observed. Severe chronic otitis interna may result in bony lysis and proliferation capable of expanding from the inner ear resulting in neurological deficits.

Aberrant Ancylostoma sp. in the brain of a dog

A 14-month-old, male American Bulldog presented to Texas A&M University Veterinary Medical Teaching Hospital in August of 2012 for anorexia, hydrophobia and gradually worsening neurologic signs. Grossly hemorrhage on the left side of the caudal cerebrum and cerebellum was observed and histologically corresponded with necrohemorrhagic and lymphoplasmacytic encephalitis associated with adult nematodes. Based on morphology and molecular analysis, these were identified as Ancylostoma sp.

Caudal Occipital Malformation Syndrome in a 6-Year-Old Female Huacaya Alpaca

A 58-kg, 6-year-old, female Huacaya alpaca presented to the Washington State University Veterinary Teaching Hospital with a history of gradual developing lethargy, reluctance to rise, anorexia, blindness, and respiratory distress. A presumptive diagnosis of dorsal displacement of the soft palate was made and a tracheostomy tube was surgically placed by the referring veterinarian. Supportive treatment included crystalloid fluids (lactated Ringer’s solution) administered IV and antimicrobial (certiofur sodium, unknown dose) therapy. The tracheotomy tube was removed and the respiratory distress appeared to have resolved. For the 2 months prior, the alpaca had been housed at an out-of-state breeding facility. Marginal feed quality during this period was believed to be related to the alpaca’s poor body condition score (1/5). The alpaca’s vaccination (Clostridium perfringens C/D, Cl. tetani toxoids) and deworming (Ivermectin) history were deemed appropriate and current. The owner thought that the alpaca might be pregnant. Upon examination, the alpaca was dull, lethargic (reluctant to rise when stimulated), and had not eaten for at least 1 day. The alpaca was thin (body condition score 1/5) and adequately hydrated. Vital signs (heart rate, respiratory rate, and temperature), capillary refill time, and mucus membrane color were normal. The alpaca urinated and defecated normally and had normal compartment 1 (C1) contractions upon auscultation. The tracheostomy site was patent, healing, and no abnormal respiratory sounds were asculted. Neurologic examination revealed an absent menace response in the left eye, with normal palpebral reflexes and pupilary light reflexes (direct and consensual). No other abnormal cranial nerve signs were detected. The alpaca held her head in an abnormally low position and moved her head slowly in response to stimuli. There were no signs of pain upon neck manipulation. Although it was difficult to maintain the alpaca in a standing position, conscious proprioceptive (CP) deficits were observed in all 4 legs. Flexor reflexes (thoracic and pelvic) and patellar reflexes were normal. Abnormalities identified on clinical pathology included decreased serum activity of SDH and AST and serum concentration of cholesterol, BUN, and albumin, most likely a result of decreased feed intake. No fecal parasite ova were observed and serum bile acids were within the normal limits. Virus neutralization testing for EHV-1, West Nile virus, and cELISA for Bluetongue virus from blood were all negative. CSF protein concentration, cell count, and cell morphology were within normal limits. Because of the continued anorexia, the alpaca was transfaunated with 2 L of rumen fluid and administered IV lactated Ringer’s solution supplemented with KCl (20 mEqs/L) and Vitamin B complex (2 mls/L) at 1.39 maintenance (4 L/d). Ceftiofur sodium (1.1 mg/kg IV q12h) and flunixin meglumine (1.1 mg/kg IV q12h) were administered. Because of the dam’s lack of milk production and substantial time spent in recumbency, the cria was weaned. Magnetic resonance imaging (MRI) examination revealed malformation of the caudal occipital bone with herniation/caudal displacement of the caudal cerebellum through the foramen magnum. There was also a T2-weighted hyperintensity within the cervical spinal cord (from C1-C3) that became hypointense on the T1-weighted images consistent with syringohydromyelia (Fig 1). Follow-up neurologic examination findings were consistent with the changes found on MRI examination. CP deficits were most likely caused by the extensive syringohydromyelia in the cervical spinal From the Department of Veterinary Clinical Sciences, Washington State University, Pullman, WA (Allen, Chen, Barrington); and is presently affiliated with Department of Veterinary Clinical Sciences, Iowa State University (Bagley). Corresponding author: Andrew J. Allen, Department of Veterinary Clinical Sciences Veterinary Teaching Hospital, P.O. Box 647060, Pullman, WA 99164-7060; e-mail: aja@vetmed.wsu.edu. Submitted August 15, 2013; Revised November 26, 2013; Accepted December 31, 2013. Copyright © 2014 by the American College of Veterinary Internal Medicine 10.1111/jvim.12316 Abbreviations:

Clinical Study of Medial Area Infarction in the Region of Posterior Inferior Cerebellar Artery

Our objective is to study the neurological characteristics of medial area infarction in the caudal cerebellum. Medial area of the caudal cerebellum is supplied with 2 branches of the posterior inferior cerebellar artery (PICA). The medial hemispheric branch of the PICA distributes to the medial area of the caudal cerebellar hemisphere. The medial branch of the PICA (mPICA) distributes to the inferior vermis. We studied the neurological characteristics of 18 patients with medial area infarction of the caudal cerebellum. The infarction was located in the medial area of the cerebellar hemisphere and vermis (medial ch/vermis) in 11 patients and in the medial area of the cerebellar hemisphere (medial ch) in 7 patients. All the 18 patients showed acute vertigo and disturbance of standing and gait at onset. On admission, the lateropulsion and wide-based gait were present in 13 patients, respectively. Mild ataxia of the extremities was shown in 7 patients. Acute vertigo and unsteadiness were prominent at onset in the 18 patients, although their ataxia of the extremities was mild or none. This result was consistent with the characteristics of medial area infarction of the caudal cerebellum. Comparing the neurological symptoms between the medial ch/vermis group and medial ch group, both lateropulsion and wide-based gait were significantly infrequent in medial ch group. This result indicated that the vermis was spared because the mPICA was not involved in the medial ch group. It is necessary to make a careful diagnosis when we encounter patients who present acute vertigo because truncal and gait ataxia are unremarkable on admission in patients with the medial area infarction of the caudal cerebellum without vermis involvement.

Branching patterns of olivocerebellar axons in relation to the compartmental organization of the cerebellum

A single olivocerebellar (OC) axon gives rise to about seven branches that terminate as climbing fibers (CFs). Branching patterns of an OC axon, which are classified into local, transverse, and longitudinal types, are highly organized, in relation to the longitudinal molecular (aldolase C or zebrin II) compartmentalization and the transverse lobulation of the cerebellum. Local branching is involved in forming a narrow band-shaped functional subarea within a molecular compartment. On the other hand, transverse and longitudinal branchings appear to be involved in linking mediolaterally separated molecular compartments and rostrocaudally separated lobular areas, respectively. Longitudinal branching occurs frequently between equivalent molecular compartments of specific combinations of lobules. These combinations include lobule V-simple lobule and crus II-paramedian lobule in the pars intermedia and hemisphere, and lobules I–V and lobule VIII in the vermis. The longitudinal branching pattern not only fits with mirror-imaged somatosensory double representation of the body in the pars intermedia, but it also suggests a general rostrocaudal link exists for the whole cerebellum across the putative rostrocaudal boundary in lobule VIc-crus I. Molecular compartments of the cerebellar cortex originate from the Purkinje cell (PC) clusters that appear in the late embryonic stage, when the immature OC projection is formed. Some clusters split rostrocaudally across crus I during the development of cortical compartments, which would result in longitudinal branching of OC projection across crus I. Supposing that the branching pattern of OC axons represents an essential organization of the cerebellum, longitudinal branching suggests a functional and developmental links between the rostral and caudal cerebellum across lobule VIc-crus I throughout the cerebellar cortex.

Distribution of Lesions in Fetal Brains Following Experimental Infection of Pregnant Sheep With Toxoplasma gondii

Six ovine fetal brains were harvested 33 to 35 days postchallenge from 5 ewes, each of which was given 3000 Toxoplasma gondii oocysts on day 90 of pregnancy. Histopathologic examination of transverse sections taken at 13 levels in the fetal brains revealed the presence of toxoplasmosis-related lesions in all 6 brains. However, lesions were not randomly distributed (P = .007); they were most numerous at the level of the optic tract, the rostral margin of the pons, and 4 mm caudal to the ansate sulcus and were absent in all sections at the level of the caudal cerebellum. Lesion distribution may be due to hemodynamic factors, differences in the expression of endothelial surface receptor molecules at the level of the blood-brain barrier, or the presence of localized permissive/inhibitory factors within the brain. The results have implications for the selection of areas of brain from aborted ovine fetuses to be examined histopathologically for laboratory diagnosis.

Distribution of a pathological form of prion protein in the brainstem and cerebellum in classical and atypical cases of bovine spongiform encephalopathy

This study evaluated the distribution and signal intensity of a prion protein resistant to proteolysis (PrP(res)) in the brainstem and cerebellum of cattle affected with classical and atypical forms of bovine spongiform encephalopathy (BSE) using a Western immunoblotting technique. In both classical and atypical cases of BSE, a stronger signal was detected in the more rostral brainstem regions relative to the obex. In classical and H-type cases a significant decrease in the PrP(res) signal was found in the cerebellum when compared to that in the obex, whereas L-type BSE cases were characterised by signals of similar intensity in these regions. The uniform distribution of PrP(res) in the region rostral to the obex suggests that when autolysed samples are being tested for BSE, both classical and atypical forms are detectable, even when this target site is missing or cannot be clearly identified. The findings indicate that both the obex and rostral brainstem can be used for BSE diagnosis whereas use of the more caudal brainstem regions and cerebellum is not recommended.

Normal and abnormal anatomy of the cerebellar vermis in midgestational human fetuses

Evaluation of the cerebellar vermis is an important component of fetal autopsy, but lack of an established approach, inadequate normal anatomic data, and the subtle nature of some cerebellar malformations negatively affect concordance between prenatal ultrasound and autopsy diagnoses. Gross anatomy and sagittal histologic sections of vermis from 26 midgestation fetuses with no posterior fossa anomalies detected by prenatal ultrasound or autopsy were examined to establish stage-specific norms. These were compared to data from three fetuses with prenatal ultrasound diagnoses of hypoplasia or absence of the cerebellar vermis, each of which had no or equivocal gross cerebellar malformation at autopsy. Two findings segregated cases from controls: (1) The ratio of the rostro-caudal length of the vermis to that of the cerebellar hemispheres was shorter for cases (<0.7), in comparison with controls (0.7-1). (2) The lobules of the vermis, particularly in the posterior lobe, were less arborized, and the nodulus (caudal-most lobule) was elongated. Prenatal sonograms from the three cases predicted more severe vermis hypoplasia than was evident at autopsy. Prenatal ultrasound images that suggest moderate-to-severe hypoplasia of the cerebellar vermis may reflect relatively subtle malformations, which are recognized histologically by direct comparison with stage-matched control data. The data in this series and others suggest a somewhat consistent pattern of lobular malformation, which affects the caudal cerebellum, particularly the nodulus, most severely. Rotation of the cerebellum, secondary to an enlarged fourth ventricle, may account for discordance between ultrasound and autopsy findings.

Vertigo due to Stroke

Episodic vertigo frequently occurs in patients suffering from transient ischemia in the distribution of the vertebrobasilar circulation (i.e., vertebrobasilar insufficiency). It may occur in isolation, with other symptoms of vertebrobasilar insufficiency or with persisting symptoms and signs of the infarction of the brain stem and/or cerebellum. Typical attacks of ischemic vertigo are abrupt in onset and last minutes. Ischemic stroke in the distribution of posterior circulation commonly develops acute onset of spontaneous prolonged vertigo and imbalance. As many as 25% of patients with risk factors for stroke who present to an emergency medical setting with isolated, severe vertigo, nystagmus, and postural instability have an infarction of the caudal cerebellum (i.e., pseudo-vestibular neuritis). Since the head thrust test can be performed at the bedside with no requirement of special equipments, it is invaluable for separating 'pseudo-vestibular neuritis' from true vestibular neuritis. Physicians who evaluate stroke patients should be trained to perform and interpret the result of the head impulse test. Since the inner ear is supplied by the vertebrobasilar circulation, inner ear symptoms are common with ischemia in the distribution. We briefly reviewed the clinical symptoms and neurological examinations of stroke presenting with vertigo, especially focusing on ischemic stroke of the vertebrobasilar territory.

Identification of aldolase C compartments in the mouse cerebellar cortex by olivocerebellar labeling

Aldolase C (zebrin II) is expressed in Purkinje cells aligned in complicated longitudinal stripe-shaped compartments. The tight link between these aldolase C compartments and the topographic olivocerebellar projection to them has made it possible to identify each compartment as a target of a specific subarea of the inferior olive and thus as a functionally distinct entity in the rat. However, it is unknown whether the overall organization of aldolase C compartments is preserved in other mammals. In this study, we tried to clarify this organization in the mouse, which is more useful in genetic studies than the rat, by identifying each aldolase C compartment in terms of the olivocerebellar projection pattern. First, aldolase C compartments were reconstructed from serial sections throughout the cerebellar cortex. Aldolase C and olivocerebellar climbing fibers were then doubly labeled by small injections of biotinylated dextran amine into various areas of the inferior olive. Climbing fibers were topographically distributed on a specific linked pair of aldolase C compartments in the rostral and caudal cerebellum. The overall relationship between aldolase C compartments and the topographic olivocerebellar projection to them in the mouse was similar to that in the rat, except for some minor differences, suggesting that the aldolase C compartments and olivocerebellar projection are organized according to a common fundamental organization in the mouse and rat. This allowed the unequivocal identification of all aldolase C compartments in the mouse by referring to the definition and nomenclature in the rat.

Light and electron microscopic analysis of KChIP and Kv4 localization in rat cerebellar granule cells

Potassium channels are key determinants of neuronal excitability. We recently identified KChIPs as a family of calcium binding proteins that coassociate and colocalize with Kv4 family potassium channels in mammalian brain (An et al. [2000] Nature 403:553). Here, we used light microscopic immunohistochemistry and multilabel immunofluorescence labeling, together with transmission electron microscopic immunohistochemistry, to examine the subcellular distribution of KChIPs and Kv4 channels in adult rat cerebellum. Light microscopic immunohistochemistry was performed on 40-microm free-floating sections using a diaminobenzidine labeling procedure. Multilabel immunofluorescence staining was performed on free-floating sections and on 1-microm ultrathin cryosections. Electron microscopic immunohistochemistry was performed using an immunoperoxidase pre-embedding labeling procedure. By light microscopy, immunoperoxidase labeling showed that Kv4.2, Kv4.3, and KChIPs 1, 3, and 4 (but not KChIP2) were expressed at high levels in cerebellar granule cells (GCs). Kv4.2 and KChIP1 were highly expressed in GCs in rostral cerebellum, whereas Kv4.3 was more highly expressed in GCs in caudal cerebellum. Immunofluorescence labeling revealed that KChIP1 and Kv4.2 are concentrated in somata of cerebellar granule cells and in synaptic glomeruli that surround synaptophysin-positive mossy fiber axon terminals. Electron microscopic analysis revealed that KChIP1 and Kv4.2 immunoreactivity is concentrated along the plasma membrane of cerebellar granule cell somata and dendrites. In synaptic glomeruli, KChIP1 and Kv4.2 immunoreactivity is concentrated along the granule cell dendritic membrane, but is not concentrated at postsynaptic densities. Taken together, these data suggest that A-type potassium channels containing Kv4.2 and KChIP1, and perhaps also KChIP3 and 4, play a critical role in regulating postsynaptic excitability at the cerebellar mossy-fiber/granule cell synapse.

Cerebral phaeohyphomycosis in a Birman kitten

Extract A 6-month-old female Birman kitten was presented for long-lasting and repeated seizures. It initially had some response to treatment but deteriorated and was euthanised. At necropsy, the brain was swollen and some of the caudal cerebellum was compressed into the foramen magnum. The right cerebral hemisphere was enlarged and had a round, dark, 5 mm-diameter focus on the dorsal surface of the rostral sigmoid gyrus of the frontal cerebrum. There were smaller dark areas extending caudally into the endomarginal gyrus. When the fixed brain was sliced transversely, the lesions were grey-coloured or translucent and involved most of the rostral half of the right cerebral hemisphere. Histologically, there was severe, extensive pyogranulomatous inflammation with some interspersed areas of spongiosus and oedema. Within the granulomas were variable numbers of branching, pigmented, thin-walled, septate fungal hyphae. Cladosporium bantianum (trichoides) was isolated from the brain. This is the most frequent agent reported from cases of cerebral phaeohyphomycosis.

Expression of the ETS transcription factor ER81 in the developing chick and mouse hindbrain

ER81 is an ETS domain-containing transcription factor, which is expressed in various developing tissues and organs of the embryo and in pools of developing spinal motor neurons and proprioceptive sensory neurons. Analysis of mice lacking ER81 function showed that this gene played an important role in the establishment of sensory-motor circuitry in the spinal cord. Here, we investigate the expression pattern of er81 in the hindbrain of both chick and mouse embryos. We find that er81 is expressed in a subpopulation of inferior olive neurons, which send their projections to the caudal cerebellum.

Phospholipase Cβ4 and Protein Kinase Cα and/or Protein Kinase CβI Are Involved in the Induction of Long Term Depression in Cerebellar Purkinje Cells

Activation of the type-1 metabotropic glutamate receptor (mGluR1) signaling pathway in the cerebellum involves activation of phospholipase C (PLC) and protein kinase C (PKC) for the induction of cerebellar long term depression (LTD). The PLC and PKC isoforms that are involved in LTD remain unclear, however. One previous study found no change in LTD in PKCgamma-deficient mice, thus, in the present study, we examined cerebellar LTD in PLCbeta4-deficient mice. Immunohistochemical and Western blot analyses of cerebellum from wild-type mice revealed that PLCbeta1 was expressed weakly and uniformly, PLCbeta2 was not detected, PLCbeta3 was expressed predominantly in caudal cerebellum (lobes 7-10), and PLCbeta4 was expressed uniformly throughout. In PLCbeta4-deficient mice, expression of total PLCbeta, the mGluR1-mediated Ca(2+) response, and LTD induction were greatly reduced in rostral cerebellum (lobes 1-6). Furthermore, we used immunohistochemistry to localize PKCalpha, -betaI, -betaII, and -gamma in mouse cerebellar Purkinje cells during LTD induction. Both PKCalpha and PKCbetaI were found to be translocated to the plasmamembrane under these conditions. Taken together, these results suggest that mGluR1-mediated activation of PLCbeta4 in rostral cerebellar Purkinje cells induced LTD via PKCalpha and/or PKCbetaI.

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.

Localization of Phospholipase Cβ Isozymes in the Mouse Cerebellum

To elucidate the role of phospholipase Cβ (PLCβ) isozymes in the cerebellum, the distributions of PLCβ3 and PLCβ4 were examined in wild-type and PLCβ4-deficient mutant mice using immunohistochemistry, and the functions were evaluated by measurement of type 1 metabotropic glutamate receptor (mGluR1)-mediated inward current and Ca2+ mobilization. In wild-type mice, PLCβ4 was distributed equally in both rostral and caudal cerebellum, while PLCβ3 was enriched in the caudal versus the rostral cerebellum. In PLCβ4-deficient mice, there was no measurable inward current or intracellular Ca2+ elevation in the rostral cerebellum, whereas small responses were observed in the caudal cerebellum. In wild-type mice, the inward current was observed only following the release of caged GTPγS, not caged IP3. These results suggest that the signal transduction machinery, including receptors, G-proteins, PLCβ3, PLCβ4, and effectors, form a functional unit, and the deletion of PLCβ4 alters this unit, markedly changing signal transduction efficacy.