Introduction - Assetsassets.cambridge.org/97805218/78135/excerpt/9780521878135_exc… · Introduction Theterminologyofcerebellarataxiasencompassesa widerangeofdisorders.Theadvancesinneuroimag-ing,

Introduction

The terminology of cerebellar ataxias encompasses awide range of disorders. The advances in neuroimag-ing, the progress in translational neurosciences, therecent discoveries in molecular biology, and the avail-ability of genetic testing have revolutionized the field ofcerebellar disorders. In particular, the identification ofthe causative mutations of many hereditary ataxias hasinfluenced daily practice worldwide. Since the clinicaldiagnosis of subtypes of ataxias is often complicated bythe salient overlap of the phenotypes between geneticsubtypes, and given the numerous disorders affectingthe cerebellum, many students, biologists, clinicians,and researchers often experience difficulties in the dis-cipline of cerebellar diseases.Making the right diagno-sis remains a major goal when facing a growing num-ber of disorders which look apparently similar. Thisbook aims to provide a framework for the diagnosisand management of cerebellar ataxias, with explana-tions on the pathophysiological basis to bridge the gapbetween basic medical sciences and clinical problems.In particular, I have reviewed the literature of these last15 years and tried to gather the most relevant infor-mation in the field, often published in papers scatteredthroughout the scientific literature. The most criticaltests to be performed are underlined.

The book is divided into 23 chapters, starting withthe embryology and anatomy of the cerebellum.Thesechapters remain essential for the appraisal of cerebel-lar ataxias. The chapter on physiology reviews the the-ories and mechanisms underlying cerebellar function.Themost commonly used clinical scales for evaluating

ataxic disorders are discussed in Chapter 4. Diagnosisand general management of cerebellar ataxias are dis-cussed in Chapters 5 and 6, respectively.The followingchapters discuss the sporadic forms and inheriteddiseases encountered in daily practice. Each chapterdescribes the disorder and its pathogenesis, empha-sizing the research aspects which have direct clinicalimplications. Autosomal recessive cerebellar ataxias,autosomal dominant cerebellar ataxias (spinocerebel-lar ataxias [SCAs]), and X-linked ataxias are reviewed.The sections on inherited ataxias have been expandedto include the most recently discovered genetic atax-ias. The last decades have brought a growing numberof demonstrations that the cerebellum participates innon-motor activities. The contributions of cerebellarcircuitry in the so-called cognitive operations, includ-ing executive functions, learning, and language, and inemotional symptoms are also discussed.

I have attempted to take into account the numer-ous comments received following the publication ofThe Cerebellum and Its Disorders in 2002. In partic-ular, I have included tables to facilitate the differen-tial diagnosis of cerebellar ataxias.Disorders occurringin children had been overlooked. They are now pre-sented, so thatmost of the cerebellar disorders relevantin a general neurologist’s practice will be explained. Ihave also attempted not to duplicate material in orderto keep the text as concise as possible. In particular,I had to be selective for the animal models of cere-bellar ataxias, selecting those with a potential clinicalapplication.

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Chapter

1 Embryology and anatomy

Embryology

Origin of the cerebellumThe cerebellum originates from the metencephalonand the caudalmesencephalon (dorsal rhombomere 1)and reaches its final configuration several months afterbirth (Koop et al., 1986; Lechtenberg, 1993).The supe-rior vermis begins to be formed at about 7 to 8 weeksof gestation, and the fusion of the inferior vermiscontinues up to about 18 weeks.The superior rhombiclip and the adjacent parts proliferate to generate therudiment of the cerebellum. The central cavity ofthe rhombencephalon becomes the fourth ventricle.In the following weeks, the cerebellum will expandrostrally, caudally, dorsally, and laterally. Cerebellarhemispheres can be identified at the fifthmonth as twolateral masses.

Transverse fissures appear progressively on the sur-face (Figure 1.1). The posterolateral fissure is the firstto appear, enabling the identification of the flocculiand the nodulus. The flocculus and the superior cere-bellar peduncle are identified at day 45 (O’Rahillyet al., 1988). The posterolateral fissure is clearly dis-cernible at week 9. At the end of the third month,the primary fissure emerges, demarcating the anteriorlobe. Two grooves can be distinguished: the secondaryfissure and the prepyramidal fissure.

Generation of cerebellar neuronsThe ventricular neuroepithelium is responsible forthe generation of nuclear cells and Purkinje cells.Interneurons of the cerebellar cortex originate fromthe metencephalon and the mesencephalon, whilegranule cells emerge solely from the external granu-lar layer (EGL) originating from the metencephalon.The migration of primitive cells over the surface ofthe cerebellum begins at about 11 to 12 weeks of ges-tation. Three stages can be identified: (1) generationof nuclear neuroblasts from the ventricular epithe-

lium, deep nuclei appearing at weeks 11 to 12, andan intense growth of dentate nuclei between week 20and week 25 (Mihajlovic & Zecevic, 1986); (2) radialoutward migration of Purkinje neuroblasts and tan-gential migration of the EGL, with the Purkinje celllayer becoming apparent between weeks 17 and 28and synapses between Purkinje cells and parallel fibersbeing formed at week 24; and (3) inward migration ofthe external granular layer starting at week 30 and per-sisting after birth. EGL cells will migrate through thePurkinje cell layer to form the internal granular layer.

During the development of the cerebellum, thenumber of Purkinje cells determines the size of thepopulation of granule neurons. Purkinje cells controlthe mitotic activity of granule cell neuroblasts withinthe EGL. Indeed, the Purkinje cell layer located under-neath the EGL continuously secretes a mitotic sig-nal sonic hedgehog (SHH), which drives the extensiveproliferation of granular cells such that granule cellsbecome the most abundant neurons in the cerebel-lum (Wechsler-Reya & Scott, 1999) (Figure 1.2). SHHalso acts on Bergmann glia differentiation. The SHHoverall expression profile in early post-natal stages isdirectly responsible for the final size of the cerebellum,being required for full lobe extent (Vaillant &Monard,2009). The external granular layer will disappear pro-gressively during the first year of life (Lechtenberg,1993).

Projections to the cerebellum display a parasagit-tal and striped organization, perpendicular to the fis-sures, forming compartments in the cerebellar cir-cuitry (Gravel & Hawkes, 1988; Voogd & Ruigrok,2004). Cells in limited regions of the inferior olive sendclimbing fibers in a band-like manner to a specificcompartment of Purkinje neurons, and mossy fibersproject to the granule cell layer in specific regionsof the bands (Hawkes et al., 1993; Zagrebelsky et al.,1997). Parasagittal bands of Purkinje neurons are pre-programmed intrinsically during development (seealso sectionThe inferior olivary complex).2






Chapter 1 – Embryology and anatomy

Figure 1.1 Genesis of fissures. The first fissure appearing is theposterolateral fissure (PLF). The second is the primary fissure (PF),which delineates the superior part of the anterior lobe. Theprepyramidal fissure (Prepyr F) and the secondary fissure (SF) appearsubsequently, followed by a development of the anterior lobe.

Figure 1.2 Development of the cerebellar cortex. SHH (Sonichedgehog, represented with red squares) is secreted by Purkinjeneurons (PN). SHH triggers the mitosis of cerebellar granularneuronal precursors in the external granular layer (EGL). SHH alsopromotes differentiation of Bergmann glia (BG). SHH acts through apatched protein and a transmembrane protein called SMO,triggering the activation of transcription factors. EGL cells willmigrate to form the internal granular layer (IGL). Adapted from:Vaillant and Monard, 2009.

Vertebrobasilar system embryogenesisThe vertebrobasilar system arises from collaterals ofthe dorsal aorta (which will give rise to the internalcarotid artery) (Padget, 1954). Three embryonic arter-ies contribute to the intracranial portions of the ver-tebrobasilar system: the trigeminal artery, the acous-tic artery, and the hypoglossal artery (Figure 1.3). Atthe cervical level, the first six segmental arteries willform the vertebral arteries. The first segmental arteryis called the proatlantal artery. At 30 days, a longitu-dinal neural artery appears on each side, supplied bythe trigeminal artery, the acoustic artery, the hypoglos-sal artery, and the proatlantal artery. At 31 days, thetwo longitudinal neural arteries merge to become the

Figure 1.3 Representationof the embryoniccarotid-vertebrobasilaranastomoses on the rightside. Abbreviations: Ao: aorta;LNA: longitudinal neuralartery; T: trigeminal artery; Ac:acoustic (otic) artery; H:hypoglossal artery; ProAtl 1:type 1 proatlantal artery;ProAtl 2: type 2 proatlantalartery. Adapted from: Pascoet al., 2004.

basilar artery. This latter communicates with the pos-terior communicating arteries originating from theinternal carotid arteries. Simultaneously, the ventraltrunks of the trigeminal, acoustic, and hypoglossalarteries disappear. The posterior-inferior cerebellarartery is a remnant of the embryological hypoglos-sal artery. At day 33, the proatlantal artery is linkedto the basilar artery by its cranial branch. The ventraltrunks of the first six segmental arteries will disappear.Disruption of the embryogenesis of the vertebrobasi-lar system leads to persistent carotid-vertebrobasilaranastomoses (Pasco et al., 2004):� The persistent trigeminal artery is found – usually

incidentally – in about 0.2% of angiograms inadults. The artery arises from the posterior side ofthe intracavernous internal carotid artery andjoins the basilar artery in its distal part. Theipsilateral vertebral artery and the proximalbasilar artery are often hypoplastic. Patients maycomplain of diplopia due to abducens nerve(nerve VI) irritation in the cavernous sinus ormay complain of facial neuralgias. Aneurysmsmay develop.

� The persistent hypoglossal artery is found in about0.05% of angiograms. It arises from the posteriorside of the cervical internal carotid in front of theC1–C2 space. The ipsilateral vertebral andposterior communicating arteries are hypoplastic.

� The persistent acoustic artery is very rare. Itoriginates from the internal carotid artery in theintrapetrous carotid canal and reaches the caudalportion of the basilar artery.

Genes, signaling, and developmentof the cerebellumSeveral genes involved in the regulation of brainand cerebellar development have been identified, in

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Figure 1.4 Cerebellar neurons are generated from twoanatomically distinct progenitor zones within the primordia.Math1 expressing neuroepithelium (rhombic lip) generatesglutamatergic neurons (red arrows). PTF1A-expressingneuroepithelium (ventricular zone) generates GABAergic neurons(blue arrows). Cells leaving the rhombic lip migrate over theanlage and form an external layer of cells which continue toproliferate. Granule neuron progenitors form the external granularlayer (EGL). Inward radial migration of EGL generates the internalgranular layer (IGL). Cerebellar Purkinje neurons are post-mitoticas they leave the ventricular zone. Adapted from: Hoshino,2006. (See color section).

particular, microcephalin, ASPM, and FOXP2 (Evanset al., 2006). Microcephalin plays a critical functionin brain size regulation during the proliferation phaseof neurogenesis. FOXP2, a transcription factor, affectsthe development of several regions of the brain. Exper-iments with mice show that FOXP2 regulates cere-bellar development and neural migration (Shu et al.,2005).

The Math1 gene encodes a transcription factorspecifically expressed in the precursors of the EGLand is required for granule cell lineage (Ben-Arieet al., 1997). All known glutamatergic neurons ofthe cerebellum derive from the Math1-positive rhom-bic lip, including unipolar brush cells and the glu-tamatergic subset of neurons in cerebellar nuclei(Figure 1.4). PTF1A (pancreas transcription fac-tor 1A) is implicated in the genesis of cerebellarGABAergic neurons (Hoshino et al., 2005). Muta-tions of the PTF1A gene on chromosome 10p13-p12.1 is associated with pancreatic and cerebellaragenesis (Sellick et al., 2004; see also Chapter 7).In absence of PTF1A, failure to generate GABAergicneurons will lead to a massive pre-natal death ofall glutamatergic neurons because the GABAergicsynaptic partners are absent (Millen & Gleeson,2008). The so-called zinc finger family of transcrip-

tion factors (ZIC) includes ZIC1, whose activity isrequired to maintain the EGL cells in a progenitorstate.

Notch proteins are transmembrane proteins whichparticipate in the process of cell-fate assignationduring development (Artavanis-Tsakonas et al., 1999).The activation of Notch signaling is dependent onthe interaction with Delta, Serrate, and Lag-2 li-gands expressed on neighboring cells. Notchundergoes proteolytic cleavages. The resulting Notch1intracellular domain translocates to the nucleus andactivates transcription of target genes involved incellular differentiation and development (Bailey &Posakony, 1995). Delta-Notch–like epidermal growthfactor–related receptor, a Notch ligand on neurons,is abundantly expressed in Purkinje neurons andmoderately expressed in granule cells. It contributesto the maturation of Bergmann glia via Purkinjeneurons–glia interactions (Eiraku et al., 2002; Saito& Takeshima, 2006). Notch1 signaling regulates theresponsiveness of progenitor cells to bone morpho-genetic proteins secreted from the roof plate of thefourth ventricle. In the absence of Notch1, cerebellarprogenitors are depleted during the early productionof hindbrain neurons, resulting in a severe decreasein the deep cerebellar nuclei that are normally bornsubsequently (Machold et al., 2007).

SHH acts on gene expression through the activ-ity of the GLI transcription factor family (Vaillant &Monard, 2009). Its transmembrane receptor Patched1 allows the translocation of a protein called SMO tothe cilia (see also Joubert syndrome in Chapter 7).SHH needs to be cholesterol-modified in order to beactive. Inhibition of this step causes abnormal devel-opment (Lanoue et al., 1997). The Smith-Lemli-Opitzsyndrome is an example of association of cerebellarhypoplasia (see also Chapter 7) and impaired choles-terol metabolism (Porter, 2008).

The reelin signaling pathway guides neuroblastmigration in the developing cerebral cortex and cere-bellum (D’Arcangelo et al., 1995). In the cerebel-lum, the granule cells secrete reelin, which guidesmigration of Purkinje neurons. Very low densitylipoprotein receptor and apolipoprotein E receptortype 2 are transmembrane receptors for reelin (see alsodysequilibrium syndrome in Chapter 20). With reelinbinding, an intracellular signaling cascade is triggered,allowing neuroblasts to complete migration and adopttheir ultimate positions in laminar structures inthe CNS.

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NeurotrophinsNeurotrophins, such as nerve growth factor, neu-rotrophin 3, and brain-derived neurotrophic factor(BDNF), play important functions in the developmentand maturation of the nervous system. Their effectsare mediated by binding to specific high-affinity tyro-sine kinase receptors (Trks). Nerve growth factor isa ligand for TrkA type receptors, BDNF targets TrkBreceptors, and neurotrophin 3 is a ligand for TrkCreceptors. BDNF is highly expressed in the cerebel-lum. Granule cells express BDNF, and both granuleand Purkinje cells express TrkB receptors (Wetmoreet al., 1990; Segal et al., 1995). BDNF is found inthe adult cerebellum, especially in Purkinje neurons.BDNF promotes survival and axonal elongation ofgranule cells and promotes survival and differentiationof Purkinje neurons (Larkfors et al., 1996). BDNF notonly regulates cerebellar post-natal development anddendritic maturation, but also participates in synapticplasticity (Richardson & Leitch, 2005). Developmentof GABAergic synapses is also under the control ofBDNF (Rico et al., 2002). Neural activity tunes therelease of neurotrophins. Therefore, neurotrophinsparticipate in activity-dependent synaptogenesis ofinhibitory synapses (Drake-Baumann, 2006).

Imaging and fetal developmentUltrasound and fetal MRI have become two majortechniques to assess cerebellar development in thefetus (Triulzi et al., 2006). The ultrasound techniquehas several advantages: easy access, low cost, porta-bility, and real-time assessment. The technique pro-vides accurate brain and ventricular morphometricmeasurements, with fairly good intra- and inter-readerreliability. Nevertheless, for the qualitative assessmentof brain parenchyma and anatomy, it is operator-dependent. It also suffers from a lack of resolution.MRI is superior to ultrasound in this regard. It is veryaccurate for identifying morphologically the develop-ment of the cerebellum. Its limitations include the res-olution, although improvements are occurring. FetalMRI allows an accurate estimation of cerebellar devel-opment from about week 19 (Figure 1.5). Vermisheight and length and cerebellar transverse diametercan be identified easily. Quantitatively, the cerebel-lum will roughly double its diameters between week19 and week 37. After 21 weeks, posterior fossa struc-tures are well defined on MRI. At this time, the tento-rium has reached its final orientation, and the typical

shape of the brainstem is recognizable. Primary fissureis well discernible in sagittal sections at week 21 or 22,and vermis folia start to be visible after week 24. FetalMRI can be used also to assess indirectly the processesof myelination and synaptogenesis. Myelination startsduring midgestation from the spinal cord to progresscranially. Sensory pathways are the first to myeli-nate. The archicerebellum and the paleocerebellumare myelinated in a newborn, while cerebellar hemi-spheres are not. T2-weighted techniques are particu-larly suited to monitor the progression of myelinationdue to the high contrast between the unmyelinated andthe myelinated white matter. A slight hypointense sig-nal can be recognized by week 21 in the deep whitematter of the cerebellum, corresponding to cerebellarnuclei.

AnatomyNomenclatureIn humans, Jansen proposed to divide the cerebellumin three parts: the anterior lobe, the posterior lobe,and the paraflocculus/flocculus (Figure 1.6). Dow hassuggested to divide the cerebellum in three areas onthe basis of the mossy fiber projections: the vestibu-locerebellum corresponds to the flocculonodular lobe,the paleocerebellum corresponds to the vermal ante-rior and posterior lobes with mainly spinal projec-tions, and the neocerebellum refers to themediolateralpart with essentially corticopontocerebellar projec-tions (Dow, 1942). The nomenclature of Larsell iswidely used in animals. The cerebellum is dividedin 10 lobules (I to X according to the nomencla-ture of Larsell), illustrated in Figures 1.6 and 1.7. Fis-sures separating the lobules are shown in Figure 1.8.Although individual lobules are easily identified in thehuman cerebellum, the overall shape of the cerebellummay vary between subjects (Diedrichsen et al., 2009).For instance, lobule IX may appear downwards nearthe opening of the foramen magnum in some sub-jects, whereas in others it will appear upwards to lob-ule VIII. The proportion of the cerebellar gray matterassigned to each lobule is illustrated in Figure 1.9. Lob-ule VII, consisting of crus I, crus II, and crus VIIb,accounts for nearly 50% of the gray matter volume(Diedrichsen et al., 2009).The left hemisphere is largerthan the right hemisphere in the majority of subjects.Anterior lobules III and IV are larger on the right side.The reverse is observed for lobule VI. This asymmetrymight be related to handedness (Snyder et al, 1995).

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A B

C D

F E

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Figure 1.5 Steps of cerebellardevelopment in the fetus on brain MRI.(A) Cerebellar development at 21 weeksgestational age (GA). MRI in the sagittal (s),transverse (t), and coronal (c) planes. Primaryfissure (black arrow) is already detectable onthe sagittal image. A slight hypointensesignal, most likely due to dentate nuclei, canbe recognized on the deep cerebellar whitematter (white arrows). (B) Cerebellardevelopment, 24 weeks GA. Primary fissure(black arrow) and cerebellar nuclei (whitearrows) are detectable. T2 hypointensity indorsal medulla and pons is also detectable(white dotted arrow). (C) Cerebellardevelopment, 28 weeks GA. A rapid increaseof vermian size (s) in comparison with A andB is well detectable. (D) Cerebellardevelopment, 31 weeks GA. Hypointensecerebellar flocculi are visible (black arrows).(E) Cerebellar development, 34 weeks GA.Cerebellar folia are easily detectable also incoronal and transverse section. (F)Measurements on brain MRI. Upper panels:Measurements of vermis height,vermis anteroposterior diameter,Transverse cerebellar diameter. Bottompanels: isolated mild inferior vermianhypoplasia detected at 20 weeks GA, andfollow-up studies at 24 and 29 weeks GAdemonstrate a progressively normaldevelopment of cerebellar vermis. From:Triulzi, 2006. With permission.

Figure 1.6 Illustration of the human cerebellum. (A) Superior view. The anterior lobe is demarcated from the posterior lobe by the primaryfissure. (B) Anterior-inferior view showing the cerebellar peduncles. The flocculonodular lobe, delineated by the posterolateral fissure, isvisible. (C) Inferior view showing the posterior part of the posterior lobe and the flocculonodular lobe. (D) Phylogenetic division of thecerebellum in paleocerebellum (medially), neocerebellum (laterally), and archicerebellum (flocculonodular lobe) represented on an unfoldedcerebellum. (E) Division in 10 lobules. (F) Components of the vermis. From: Colin et al., 2002. With permission. (See color section).

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Figure 1.7 Parcellation of the cerebellum in individual lobules.Upper panels, coronal sections; lower left, parasagittal section; lowerright, inferior view of the cerebellum. (See color section).

Figure 1.8 Lobules of the cerebellum in a coronal section and thecorresponding fissures.

Figure 1.9 Volume of lobules in percentage of the total estimated cerebellar gray matter volume in healthy adults (total = 100%). Volumesof left and right side are considered together. Adapted from: Diedrichsen et al., 2009. (See color section).

The cerebellum is highly stereotyped in its cellularcircuitry, but the organization of input–output path-ways differs according to the cerebellar region, leadingto a functional compartmentalization.

Afferent fibersThree pairs of cerebellar peduncles allow the affer-ent fibers to reach their targets: the inferior cerebel-lar peduncle (also called restiform body), the middlecerebellar peduncle (brachium pontis), and the supe-rior cerebellar peduncle (brachium conjunctivum).Tracts passing through the cerebellar peduncles arelisted in Table 1.1. The number of afferent fibers isvery high as compared with cerebellar efferent fibers(ratio of about 40:1). The cerebellum receives threetypes of fibers: climbing fibers emerging exclusivelyfrom the contralateral inferior olive and ascending inthe inferior cerebellar peduncle, mossy fibers arisingfrom a large number of sources, and the diffusely dis-tributed cholinergic/monoaminergic afferents (oftencalled “the third afferent system”). While climbingfibers are thin and relatively slow-conducting fibers,mossy fibers are large and fast conducting fibers (Colinet al., 2002; see also Chapter 2).

The afferent synaptic projections are organized inparasagittal stripes: (1) mossy fiber inputs from the

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Table 1.1 Tracts passing in the cerebellar peduncles

Peduncle Afferents Efferents

Inferior cerebellar peduncle (restiform body) Olivocerebellar tractVestibulocerebellar tractCuneocerebellar tracta

Reticulocerebellar tractDorsal spinocerebellar tracta

Trigeminocerebellar tract

Cerebelloolivary tractCerebellovestibular tractCerebellospinal tractCerebelloreticular tract

Middle cerebellar peduncle (brachium pontis) Pontocerebellar tract

Superior cerebellar tract(brachium conjunctivum)

Ventral spinocerebellar tractb

Tectocerebellar tractDentatorubral tractCerebellotegmental tractCerebellovestibular tractCerebelloolivary tract

aUncrossed. bCrossed.

spinocerebellar and cuneocerebellar tracts, (2) stripedmuscarinergic receptors in the Purkinje and molec-ular layers complemented with mossy fiber rosettesstained with acetylcholinesterase, and (3) zonal andprealbumin/calcitonin gene-related peptide reactiveclimbing fiber inputs (Hamamura et al., 2004). Stripesof these inputs alternate and monoclonal antibodiesagainst a membrane fraction clearly show a parasagit-tal stripe organization of Purkinje neurons, with alter-nating zebrin-positive and -negative bands. Thesezebrin compartments could represent a fundamentalunit of organization in the cerebellum (see also sectionThe inferior olivary complex).

Cerebellar circuitryThe cerebellum is highly stereotyped in its cellular cir-cuitry (Figure 1.10). The highly folded cerebellar cor-tex projects to (relatively) small nuclei, the sole outputof the cerebellum.

The cerebellar cortexPurkinje neuronsThe cerebellar cortex is divided in three layers.Purkinje cells make a monolayer (ganglionic), whichseparates the molecular layer (outer) from the innergranular layer. The estimation of the number of Pur-kinje neurons for a human cerebellum is about 15 mil-lion. These neurons have a typical pear-shaped soma,with a single axon leaving the lower pole. The agran-ular endoplasmic reticulum is extremely developed.Its membrane contains inositol 1,4,5-triphosphate andryanodine receptors. In the granular layer, numerouscollaterals are oriented perpendicularly to the axis of

the folium. Purkinje neurons are GABAergic (Ito &Yoshida, 1964). They inhibit deep nuclei and vestibu-lar nuclei. Also, branches of the supra-ganglionic andinfra-ganglionic plexus inhibit the basket/stellate cellsand the Golgi/Lugaro cells, respectively.

The primary dendrite emerging from the outerpole makes an arbor, with the terminal part of thedendrite being covered by numerous spines makingexcitatory synapses with parallel fibers. Purkinje neu-rons have one of themost extensive dendritic domains,composed of a dense network of spines along dis-tal shafts. Climbing fibers target Purkinje neuronsin an exclusive one-to-one relationship. The connec-tion between one ascending climbing fiber and a Pur-kinje neuron represents a very powerful synapse (seeChapter 2).

Granule cellsGranule cells have an oval shape, with typical nakednuclei due to the thinness of the cytoplasm. There areabout 3 to 7 million granule cells/mm3 in humans,which equals between 1010 and 1011 cells/cerebellum.Terminals of mossy fibers end up in the granular layer,giving rise to clubby enlargements, called “rosettes”(Figure 1.11), which are parts of a complex globularenlargement (glomerulus). Rosettes give rise to special“en marron” excitatory synaptic contacts with termi-nal branches of the granule cell dendrites. One rosettemakes about 90 to 100 synapses with dendrites, witheach granule cell presenting four to five dendrites.Axons of Golgi neurons make inhibitory synapses onthe branches of the granule dendrites. Granule cellsare the origin of an ascending thin axon which pene-trates in themolecular layer to bifurcate in two parallel

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A

B

pf Bc

Lc

Gc

br. c

CF

MF

ST

IO

CN

PN

mf

: +: −

Gran. c

Sc

Figure 1.10 Wiring and connections of the cerebellar circuitry. (A) Mossy fibers (blue) and climbing fibers (red) project to cerebellar cortex(gray area) and cerebellar nuclei. The Purkinje neuron interacts with granule cells and inhibitory interneurons of the cerebellar cortex. Purkinjecells represent the output of the cerebellar cortex. Purkinje neurons inhibit cerebellar nuclei, which are the origin of the output emergingfrom the cerebellum. (B) Neurons of cerebellar circuitry. Abbreviations: MF: mossy fiber; CF: climbing fiber; IO: inferior olive; Gran. c: granulecell; br. c: brush cell; Gc: Golgi cell; Lc: Lugaro cell; Bc: basket cell; Sc: stellate cell; PN: Purkinje neuron; CN: cerebellar nuclei.+: excitatory; – : inhibitory. (See color section.)

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Figure 1.11 The glomerulus. The enlarged extremity of a mossyfiber (represented in yellow), called “rosette,” is connected withdendrites of the granule cells (shown in blue) and a Golgi cell(illustrated in green). It also receives an axonal projection from thelatter. Therefore, Golgi cells regulate mossy fiber inputs. Golgi cellsare themselves excited by parallel fibers emerging from the granulecells. (See color section.)

branches running parallel to the axis of the folium inopposite directions. Parallel fibers have a diameter ofabout 0.25 �m, with a length estimated at 2 to 7 mm.Varicose swellings form excitatory synapses with den-dritic spines of Purkinje neurons, which are dynamicsmall protuberances bearing the postsynaptic compo-nents of the synapses. Their shape and number aresensitive to numerous physiological conditions, suchas learning (Federmeier et al., 2002). Parallel fibersliberate nitric oxide (NO), which activates guanylate-cyclase.

Unipolar brush cellsUnipolar brush cells are found in the granular layer.Their size is between a granule cell and a Golgi cell(Mugnaini & Floris, 1994). They are densely stainedwith anti-serum against calretinin, a calcium-bindingprotein. A main feature of unipolar brush cells is theirthick dendrite terminating in a brush-like tip, hencetheir name. They are found mainly in the vestibulo-cerebellum and the lingula. Their density is moderate-to-low in other folia of the vermis and in the interme-diate cortex. They are found rarely in lateral regionsof the cerebellum. Mossy fiber terminals form a spe-cial synapse with the dendrites of unipolar brush cells.There is a long synaptic cleft, with many sites of vesicleclustering.The neurotransmitter is trapped in the cleft,a single spike in the mossy fiber producing a 500-msecspike burst.The axons branch in the granular layer andend with a rosette.

Inhibitory interneuronsInhibitory interneurons are located in the molecularand granular layers. Basket cells are located just abovethe Purkinje layer. Their dendrites have long spines.The axon runs perpendicular to the long axis of thefolium above Purkinje neurons and gives off descend-ing collaterals surrounding the Purkinje cell soma in abasket-like shape. The end of the basket connects withthe Purkinje cell in a structure called “pinceau.”This isan inhibitory synapse, one basket cell inhibiting up tonine Purkinje neurons. Stellate cells occupy the outertwo-thirds of the molecular layer. They have a shortaxon. Their dendrites make inhibitory synapses withthe Purkinje cell dendrites outside the basket. Golgicells and stellate cells share parallel fiber inputs withthe Purkinje neurons. Golgi cells are inhibited by col-laterals of Purkinje neurons and inhibit the synaptictransmission betweenmossy fiber rosettes and granulecell dendrites, regulating mossy fiber inputs. Lugarocells are characterized by a small fusiform soma and adendrite expanding horizontally under Purkinje cells.Both their soma and dendrites receive amassive inner-vation from collaterals of the axon of Purkinje neu-rons. Lugaro cells have an ascending axon, makingnumerous inhibitory synapses with the soma and den-drites of basket and stellate cells.

Bergmann glial cellsBergmann glial cells are specialized astrocytes closelyassociated with Purkinje cells. Astrocytes are exten-sively coupled by gap junctions (Giaume &McCarthy,1996). These latter participate in electrical couplingand intercellular signaling. They are formed by twohemichannels, each of which comprises six proteinsubunits called connexins. Connexin43 (Cx43), themajor constituent of astrocytic gap junctions, is highlyexpressed in astrocytes throughout the brain. Anothergroup of proteins, called pannexins and contributingto gap junctions, are expressed in particular in Pur-kinje cells.

Cerebellar nucleiThe cerebellar nuclei are the main target of Purkinjeneurons. In humans, the medial nucleus correspondsto the fastigial nucleus, the globosus/emboliformis tothe anterior/posterior interpositus nucleus, and thelateral nucleus to the dentate nucleus. This latter con-tains the majority of neurons. It looks like a foldedband, with a hilus located medially. It can be identified

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Introduction - Assetsassets.cambridge.org/97805218/78135/excerpt/9780521878135_exc… · Introduction Theterminologyofcerebellarataxiasencompassesa widerangeofdisorders.Theadvancesinneuroimag-ing,