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This was a study of 12 cerebellar cortical dysplasias (CCDs) fetuses, these cases were characterized by a disorder of cerebellar fissures. Historically, CCD diagnosis was primarily performed using postnatal imaging. Unique to this study was the case series of CCD for prenatal diagnosis using prenatal ultrasound, as well as we found that AXIN1 and FOXC1 mutations may be related to CCD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Lysosomal acid phosphatase 2 ( Acp2 ) mutant mice (naked-ataxia, nax ) have a severe cerebellar cortex defect with a striking reduction in the number of granule cells. Using a combination of in vivo and in vitro immunohistochemistry, Western blotting, BrdU assays, and RT-qPCR, we show downregulation of MYCN and dysregulation of the SHH signaling pathway in the nax cerebellum. MYCN protein expression is significantly reduced at P10, but not at the peak of proliferation at around P6 when the number of granule cells is strikingly reduced in the nax cerebellum. Despite the significant role of the SHH-MycN pathway in granule cell proliferation, our study suggests that a broader molecular pathway and additional mechanisms regulating granule cell development during the clonal expansion period are impaired in the nax cerebellum. In particular, our results indicate that downregulation of the protein synthesis machinery may contribute to the reduced number of granule cells in the nax cerebellum.

Chromosomal microarray analysis is commonly used as screening test for children with neurodevelopmental issues, also in case of complex neurological phenotypes. Developmental delay/intellectual disability is a common presentation sign in pediatric ataxias, diseases with high clinical and genetic heterogeneity. In order to determine the diagnostic yield of Array-CGH in such conditions, all the tests performed in the last 10-year activity of a single referral center in children who present, besides the neurodevelopmental impairment, cerebellar abnormalities have been systematically gathered. The study demonstrates that, except for Dandy-Walker malformation or poly-malformative phenotypes, chromosomal microarray analysis should be discouraged as first-line diagnostic test in pediatric ataxias with neurodevelopmental disability.

Cerebellar dysplasia with cysts (CDC) is an imaging finding typically seen in combination with cobblestone cortex and congenital muscular dystrophy in individuals with dystroglycanopathies. More recently, CDC was reported in seven children without neuromuscular involvement (Poretti-Boltshauser syndrome). Using a combination of homozygosity mapping and whole-exome sequencing, we identified biallelic mutations in LAMA1 as the cause of CDC in seven affected individuals (from five families) independent from those included in the phenotypic description of Poretti-Boltshauser syndrome. Most of these individuals also have high myopia, and some have retinal dystrophy and patchy increased T2-weighted fluid-attenuated inversion recovery (T2/FLAIR) signal in cortical white matter. In one additional family, we identified two siblings who have truncating LAMA1 mutations in combination with retinal dystrophy and mild cerebellar dysplasia without cysts, indicating that cysts are not an obligate feature associated with loss of LAMA1 function. This work expands the phenotypic spectrum associated with the lamininopathy disorders and highlights the tissue-specific roles played by different laminin-encoding genes., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Traditionally, subcortical structures such as the cerebellum are supposed to exert a modulatory effect on epileptic seizures, rather than being the primary seizure generator. We report a 14-month old girl presenting, since birth, with seizures symptomatic of a right cerebellar dysplasia, manifested as paroxystic contralateral hemifacial spasm and ipsilateral facial weakness. Multimodal imaging was used to investigate both anatomical landmarks related to the cerebellar lesion and mechanisms underlying seizure generation. Electric source imaging (ESI) supported the hypothesis of a right cerebellar epileptogenic generator in concordance with nuclear imaging findings; subsequently validated by intra-operative intralesional recordings. Diffusion spectrum imaging-related tractography (DSI) showed severe cerebellar structural abnormalities confirmed by histological examination. We suggest that hemispheric cerebellar lesions in cases like this are likely to cause epilepsy via an effect on the facial nuclei through ipsilateral and contralateral aberrant connections., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Methods for generating loss-of-function mutations, such as conventional or conditional gene knockout, are widely used in deciphering gene function in vivo. By contrast, inducible and reversible regulation of endogenous gene expression has not been well established. Using a mouse model, we demonstrate that a chimeric transcriptional repressor molecule (tTS) can reversibly inhibit the expression of an endogenous gene, Nmyc. In this system, a tetracycline response element (TRE) artificially inserted near the target gene's promoter region turns the gene on and off in a tetracycline-inducible manner. Nmyc(TRE) mice were generated by inserting a TRE into the first intron of Nmyc by the knockin technique. Nmyc(TRE) mice were crossed to tTS transgenic mice to produce Nmyc(TRE/TRE): tTS embryos. In these embryos, tTS blocked Nmyc expression, and embryonic lethality was observed at E11.5d. When the dam was exposed to drinking water containing doxycycline (dox), normal endogenous Nmyc expression was rescued, and the embryo survived to birth. This novel genetic modification strategy based on the tTS-dox system for inducible and reversible regulation of endogenous mouse genes will be a powerful tool to investigate target genes that cause embryonic lethality or other defects where reversible regulation or temporary shutdown of the target gene is needed.

The present study examined the spatial organization of tyrosine hydroxylase (TH) immunopositive Purkinje cells in the cerebellum of rolling mouse Nagoya with reference to the distribution pattern of the cerebellar compartmentation antigen, heat shock protein 25 (HSP25). Whole-mount immunostaining revealed a striking pattern of parasagittal stripes of TH staining in the rolling mouse cerebellum but not in the control cerebellum. Although the TH stripes resembled the zebrin II stripes in the rolling cerebellum, these two distributions did not completely overlap. The TH stripes were present in the lobules VI and VII (central zone), the lobule X (nodular zone), and the paraflocculus, where zebrin II immunostaining was uniformly expressed. Double immunostaining revealed that TH stripes were aligned in an alternative fashion with HSP25 stripes within the caudal half of lobule VIb, lobules IXb and X, and paraflocculus. Some, but not all, TH stripes shared boundaries with HSP25 stripes. These results revealed an alternating array of TH immunopositive Purkinje cell subsets with HSP25 immunopositive Purkinje cells in the zebrin II-defined transverse zone of the rolling mouse cerebellum. The constitutive expression of HSP25 may prevent the ectopic expression of TH in zebrin II immunopositive Purkinje cell subsets., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Opitz G/BBB syndrome (OS) is a genetic disorder characterized by midline developmental defects. Male patients with the X-linked form of OS, caused by loss-of-function mutations in the MID1 gene, show high variability of the clinical signs. MID1 encodes a ubiquitin ligase that controls phosphatase 2A, but its role in the pathogenesis of the disease is still unclear. Here, we report a mouse line carrying a nonfunctional ortholog of the human MID1 gene, Mid1. Mid1-null mice show the brain anatomical defect observed in patients (i.e., hypoplasia of the anterior portion of the medial cerebellum, the vermis). We found that the presence of this defect correlates with motor coordination and procedural and nonassociative learning impairments. The defect is limited to the most anterior lobes of the vermis, the region of the developing cerebellum adjacent to the dorsal midbrain. Analyses at midgestation reveal that lack of Mid1 causes the shortening of the posterior dorsal midbrain, the rostralization of the midbrain/cerebellum boundary, and the downregulation of a key player in the development of this region, Fgf17. Thus, lack of Mid1 causes a misspecification of the midbrain/cerebellar boundary that results in an abnormal development of the most anterior cerebellar lobes. This animal model provides a tool for additional in vivo studies of the physiological and pathological role of the Mid1 gene and a system to investigate the development and function of anterior cerebellar domains.

Transcription factors of the Nuclear Factor I (Nfi) family are important for the development of specific neuronal and glial populations in the nervous system. One such population, the neurons of the basilar pontine nuclei, expresses high levels of Nfi proteins, and the pontine nuclei are greatly reduced in mice lacking a functional Nfib gene. Pontine neurons, along with other precerebellar neurons that populate the hindbrain, arise from precursors in the lower rhombic lip and migrate anteroventrally to reach their final location. Using immunohistochemistry, we find that NFI-B expression is specific for mossy fiber populations of the precerebellar system. Analysis of the Nfib(-/-) hindbrain indicates that the development of the basilar pontine nuclei is delayed, with pontine neurons migrating 1-2 days later than in control animals, and that significantly fewer pontine neurons are produced. While the mossy fiber nuclei of the caudal medulla do form, they also exhibit a developmental delay. Nfia and Nfix null mice exhibit no apparent pontine phenotype, implying specificity in the action of NFI family members. Collectively, these data demonstrate that Nfib plays an important role in the generation of precerebellar mossy fiber neurons, and may do so at least in part by regulating neurogenesis.

Ts65Dn mice are a genetic model for Down syndrome. Among others, these mice have cerebellar pathology features which parallel those seen in Down syndrome patients. Both individuals with Down syndrome and Ts65Dn mice have reduced cerebellar volume and numbers of granule and Purkinje cells. In this report, we describe morphological abnormalities of axons of Purkinje cells in the cerebellum of Ts65Dn mice, by using anti-calbindin immunocytochemistry. A consistent number of Purkinje cells shows axons bearing giant varicosities along their transit through the granular layer. The cerebellar arbor vitae made by fasciculated Purkinje cell axons has a patchy appearance, some tracks being devoid of calbindin staining. The infraganglionic plexus, formed by recurrent collaterals of Purkinje cell axons, has enormously increased density, which is evidence for a compensatory reaction to degeneration of distal segments of axons. These alterations are accompanied by strong glial reaction as evidenced by GFAP immunocytochemistry. Moreover, the alterations are more consistent in the anterior lobules of the vermis and intermediate cortex. The axonal pathology of Purkinje cells may explain the impairment in cerebellar functions observed in Ts65Dn mice at the adulthood.

TrkB, the cognate receptor for brain-derived neurotrophic factor and neurotrophin-4, has been implicated in regulating synapse formation in the central nervous system. Here we asked whether TrkB plays a role in the maturation of the climbing fibre-Purkinje cell (CF-PC) synapse. In rodent cerebellum, Purkinje cells are initially innervated by multiple climbing fibres that are subsequently culled to assume the mature mono-innervated state, and whose contacts translocate from the soma to the dendrites. By employing transgenic mice hypomorphic or null for TrkB expression, our results indicated that perturbation of TrkB in the immature cerebellum resulted in ataxia, that Purkinje cells remained multiply innervated by climbing fibres beyond the normal developmental time frame, and that synaptic transmission at the parallel fibre-Purkinje cell synapse remained functionally unaltered. Mechanistically, we present evidence that attributes the persistence of multiple climbing fibre innervation to an obscured discrimination of relative strengths among competing climbing fibres. Soma-to-dendrite translocation of climbing fibre terminals was unaffected. Thus, TrkB regulates pruning but not translocation of nascent CF-PC synaptic contacts.

Medulloblastoma, the most common brain tumor in childhood, appears to originate from cerebellar granule cell precursors (GCPs), located in the external granular layer (EGL) of the cerebellum. The antiproliferative gene PC3 (Tis21/BTG2) promotes cerebellar neurogenesis by inducing GCPs to shift from proliferation to differentiation. To assess whether PC3 can prevent the neoplastic transformation of GCPs and medulloblastoma development, we crossed transgenic mice conditionally expressing PC3 (TgPC3) in GCPs with Patched1 heterozygous mice (Ptc(+/-)), a model of medulloblastoma pathogenesis characterized by hyperactivation of the Sonic Hedgehog pathway. Perinatal up-regulation of PC3 in Ptc(+/-)/TgPC3 mice results in a decrease of medulloblastoma incidence of approximately 40% and in a marked reduction of preneoplastic abnormalities, such as hyperplastic EGL areas and lesions. Moreover, overexpression of cyclin D1, hyperproliferation, and defective differentiation--observed in Ptc(+/-) GCPs--are restored to normality in Ptc(+/-)/TgPC3 mice. The PC3-mediated inhibition of cyclin D1 expression correlates with recruitment of PC3 to the cyclin D1 promoter, which is accompanied by histone deacetylation. Remarkably, down-regulation of PC3 is observed in preneoplastic lesions, as well as in human and murine medulloblastomas. As a whole, this indicates that PC3 may prevent medulloblastoma development by controlling cell cycle and promoting differentiation of GCPs.

Myosin Va is an actin-based molecular motor that is involved in organelle transport and membrane trafficking. Here, we explored the role of myosin Va in the formation of synaptic circuitry by examining climbing fiber (CF) innervation of Purkinje cells (PCs) in the cerebella of dilute-neurological (d-n) mice and dilute-opisthotonus (dop) rats that have mutations in dilute-encoded myosin Va. Anterograde labeling of CFs with biotinylated dextran amine (BDA) revealed that they arborized poorly and that their tips extended only half way through the thickness of the molecular layer (ML) in adult d-n mice. Using immunohistochemistry specific for vesicular glutamate transporter 2 (VGluT2) to visualize CF synaptic terminals, we found that during development and in adulthood, these terminals did not ascend as far along the proximal shaft dendrites of PCs in d-n mice and dop rats as they did in normal animals. An irregular distribution of BDA-labeled bulbous varicosities and VGluT2 spots along CF branches were also noted in these animals. Finally, VGluT2-positive CF terminals were occasionally localized on the PC somata of adult d-n cerebella. These phenotypes are consistent with our electrophysiological findings that CF-mediated excitatory postsynaptic currents (EPSCs) were significantly smaller in amplitude and faster in decay in adult d-n mice, and that the regression of multiple CFs was slightly delayed in developing d-n mice. Taken together, our results suggest that myosin Va is essential for terminal CF extension and for the establishment of CF synapses within the proper dendritic territories of PCs.

We demonstrate here that integrin-linked kinase (ILK), a serine/threonine kinase that binds to the beta1 integrin cytoplasmic domain, regulates cerebellar development. Mice with a CNS-restricted knock-out of the Ilk gene show perturbations in the laminar structure of the cerebellar cortex that are associated with defects in Bergmann glial fibers and the formation of meningeal basement membranes. Similar defects have been observed in mice lacking beta1 integrins in the CNS. ILK and beta1 integrins are coexpressed in Bergmann glial cells, and studies with primary cells in culture demonstrate that ILK and CDC42 are required for beta1-integrin-dependent glial process outgrowth. Consistent with these findings, the amount of GTP-bound CDC42 is impaired in the cerebellum of Ilk-deficient mice. We conclude that beta1 integrin, ILK and CDC42 are components of the signaling machinery that regulates glial process outgrowth in the cerebellum. We also show that granule cell precursor proliferation is affected in ILK-deficient mice, but our findings provide strong evidence that proliferative defects are a secondary consequence of ILK function in glia.

The Lurcher mutation in the Grid2 gene causes the cell autonomous death of virtually all cerebellar Purkinje cells and the target-related death of 90% of the granule cells and 60-75% of the olivary neurons. Inactivation of Bax, a pro-apoptotic gene of the Bcl-2 family, in heterozygous Lurcher mutants (Grid2Lc/+) rescues approximately 60% of the granule cells, but does not rescue Purkinje or olivary neurons. Given the larger size of the cerebellar molecular layer in Grid2Lc/+;Bax(-/-) double mutants compared to Grid2Lc/+ mutants, we analyzed the survival of the stellate and basket interneurons as well as the synaptic connectivity of parallel fibers originating from the surviving granule cells in the absence of their Purkinje cell targets in the Grid2Lc/+;Bax(-/-) cerebellum. Quantification showed a significantly higher density of interneurons ( approximately 60%) in the molecular layer of the Grid2Lc/+;Bax(-/-) mice compared to Grid2Lc/+, suggesting that interneurons are subject to a BAX-dependent target-related death in the Lurcher mutants. Furthermore, electron microscopy showed the normal ultrastructural aspect of a number of parallel fibers in the molecular layer of the Grid2Lc/+; Bax(-/-) double mutant mice and preserved their numerous synaptic contacts on interneurons, suggesting that interneurons could play a trophic role for axon terminals of surviving granule cells. Finally, parallel fibers varicosities in the double mutant established "pseudo-synapses" on glia as well as displayed autophagic profiles, suggesting that the connections established by the parallel fibers in the absence of their Purkinje cell targets were subject to a high turnover involving autophagy., (Copyright 2006 Wiley-Liss, Inc.)

Synapse formation and maintenance require extensive transsynaptic interactions involving multiple signal transduction pathways. In the cerebellum, Purkinje cells (PCs) receive GABAergic, axo-dendritic synapses from stellate cells and axo-somatic synapses from basket cells, both with GABAA receptors containing the alpha1 subunit. Here, we investigated the effects of a targeted deletion of the alpha1 subunit gene on GABAergic synaptogenesis in PCs, using electrophysiology and immunoelectron microscopy. Whole-cell patch-clamp recordings in acute slices revealed that PCs from alpha1(0/0) mice lack spontaneous and evoked IPSCs, demonstrating that assembly of functional GABAA receptors requires the alpha1 subunit. Ultrastructurally, stellate cell synapses on PC dendrites were reduced by 75%, whereas basket cell synapses on the soma were not affected, despite the lack of GABAA-mediated synaptic transmission. Most strikingly, GABAergic terminals were retained in the molecular layer of adult alpha1(0/0) mice and formed heterologous synapses with PC spines characterized by a well differentiated asymmetric postsynaptic density. These synapses lacked presynaptic glutamatergic markers and postsynaptic AMPA-type glutamate receptors but contained delta2-glutamate receptors. During postnatal development, initial steps of GABAergic synapse formation were qualitatively normal, and heterologous synapses appeared in parallel with maturation of dendritic spines. These results suggest that synapse formation in the cerebellum is governed by neurotransmitter-independent mechanisms. However, in the absence of GABAA-mediated transmission, GABAergic terminals in the molecular layer apparently become responsive to synaptogenic signals from PC spines and form stable heterologous synapses. In contrast, maintenance of axo-somatic GABAergic synapses does not depend on functional GABAA receptors, suggesting differential regulation in distinct subcellular compartments.

The object of our report is the presentation of the morphological picture of cerebellar cortex malformation as a sequel of disturbed neuronal migration. In the disarranged tissue, cavities with a network of meningeal tissue and embedded pathological vessels were noted. The external granule cells did not form a proper external granule layer, but moved deeper, forming irregular aggregates. Abnormally aggregated external granular cells invaded the cerebellar tissue. Abnormal Purkinje cell positioning and a disarranged molecular layer were observed. The normal layered pattern of the cerebellar cortex was disorganized. The presented cases represent a spectrum of morphological changes which are the consequence of aberrant migration. Against a background of vascular pathology affecting the meningoglial network the migration pathways were disrupted. The defective movement of neurons and their faulty maturation resulted in disturbances of cortical layering, and defects of cerebellar folia formation.

Fukuyama-type congenital muscular dystrophy (FCMD) is characterized by muscular dystrophy and cortical dysgenesis of the cerebrum and cerebellum. We investigated the extent and nature of tauopathy in the brains of 7 postfetal (14-34 years of age) and 2 fetal (18- and 20-week gestational age) FCMD cases. In all postfetal cases, tauopathy was found in the areas of cortical dysgenesis in the cerebrum, in addition to predictable sites such as the hippocampus. In fetal cases, the neuropil of malformed cerebral cortex was diffusely immunostained with anti-aberrantly phosphorylated tau antibodies. By immunoelectron microscopy, the epitope of the antibodies was associated with microtubule-like bundles within cellular processes protruding through disrupted glia limitans. In Western blot analysis, a unique 50-kDa band of tau was detected in a fetal and a postfetal case. In addition, 3 to 4 tau bands of 60 to 68 kD, similar to tau in Alzheimer disease, were also detected in the latter. After dephosphorylation, the insoluble tau from the fetal and the postfetal cases showed highly similar immunoblotting patterns. This anomalous phosphorylation of tau may be related to the development of the cortical dysgenesis in FCMD and may shed light on the biologic function of tau in the development of the central nervous system.

Neurobiology of speech and language has previously been studied in the KE family, in which half of the members have severe impairment in both speech and language. The gene responsible for the phenotype was mapped to chromosome 7q31 and identified as the FOXP2 gene, coding for a transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain. Because of linkage studies implicating 7q31 in autism, where language impairment is a component of the disorder, and in specific language impairment, FOXP2 has also been considered as a potential susceptibility locus for the language deficits in autism and/or specific language impairment. In this study, we characterized mice with a disruption in the murine Foxp2 gene. Disruption of both copies of the Foxp2 gene caused severe motor impairment, premature death, and an absence of ultrasonic vocalizations that are elicited when pups are removed from their mothers. Disruption of a single copy of the gene led to modest developmental delay but a significant alteration in ultrasonic vocalization in response to such separation. Learning and memory appear normal in the heterozygous animals. Cerebellar abnormalities were observed in mice with disruptions in Foxp2, with Purkinje cells particularly affected. Our findings support a role for Foxp2 in cerebellar development and in a developmental process that subsumes social communication functions in diverse organisms.

Wnt signaling regulates hippocampal development but little is known about the functions of specific Wnt receptors in this structure. Frizzled 9 is selectively expressed in the hippocampus and is one of about 20 genes typically deleted in Williams syndrome. Since Williams syndrome is associated with severe visuospatial processing defects, we generated a targeted null allele for frizzled 9 to examine its role in hippocampal development. Frizzled 9-null mice had generally normal gross anatomical hippocampal organization but showed large increases in apoptotic cell death in the developing dentate gyrus. This increase in programmed cell death commenced with the onset of dentate gyrus development and persisted into the first postnatal week of life. There was also a perhaps compensatory increase in the number of dividing precursors in the dentate gyrus, which may have been a compensatory response to the increased cell death. These changes in the mutants resulted in a moderate decrease in the number of adult dentate granule cells in null mice and an increase in the number of hilar mossy cells. Heterozygous mice (the same frizzled 9 genotype as Williams syndrome patients) were intermediate between wild type and null mice for all developmental neuronanatomic defects. All mice with a mutant allele had diminished seizure thresholds, and frizzled 9 null mice had severe deficits on tests of visuospatial learning/memory. We conclude that frizzled 9 is a critical determinant of hippocampal development and is very likely to be a contributing factor to the neurodevelopmental and behavioral phenotype of patients with Williams syndrome.

When evaluating children with mental retardation, subtle cerebral and cerebellar morphologic anomalies are often noted at Magnetic Resonance Imaging (MRI). Some, such as cerebellar cortical dysplasia (CCD), have been considered as subtle markers of cerebral dysgenesis. Their functional significance and their effect on brain function, remain unknown. To study supratentorial functional disturbances related to CCD we performed Positron-Emission-Tomography (PET) studies in two children with isolated CCD, in order to investigate the degree of involvement of supratentorial structures. One had developmental delay, motor disturbances and ataxia, and the other one only had mental retardation. PET studies revealed hypoperfusion and hypometabolism within the vermis, thalamus and the right striatum in one case, and hypometabolism in the basal ganglia and cerebellar deep grey nuclei in the other case. Our results could lead to a hypothesis explaining motor disturbances as well as cognitive impairment, and could suggest a pathological functional significance of CCD. Nevertheless, the relationship between these findings and mental retardation needs further investigation.

The formation of neuronal networks in the central nervous system (CNS) requires precise control of axonal branch development and stabilization. Here we show that cell-specific ablation of the murine gene Ptk2 (more commonly known as fak), encoding focal adhesion kinase (FAK), increases the number of axonal terminals and synapses formed by neurons in vivo. Consistent with this, fak mutant neurons also form greater numbers of axonal branches in culture because they have increased branch formation and reduced branch retraction. Expression of wild-type FAK, but not that of several FAK variants that prevent interactions with regulators of Rho family GTPases including the p190 Rho guanine nuclear exchange factor (p190RhoGEF), rescues the axonal arborization phenotype observed in fak mutant neurons. In addition, expression of a mutant p190RhoGEF that cannot associate with FAK results in a phenotype very similar to that of neurons lacking FAK. Thus, FAK functions as a negative regulator of axonal branching and synapse formation, and it seems to exert its actions, in part, through Rho family GTPases.

The staggerer (sg) mutant mouse shows an early block in Purkinje cell (PC) development due to a truncation of the transcription factor retinoic acid-related orphan receptor alpha (ROR alpha). Cerebellar cultures from neonatal sg mice recapitulate many in vivo postnatal changes in PCs and allow for detailed observation of sequential dendritic outgrowth and gene expression changes. In addition, this in vitro system provides a tractable basis for ROR alpha replacement studies.

Because it is now possible to obtain high-resolution multiplanar MR imaging of the cerebellum and because of the developing interest on the role of the cerebellum on higher brain functions, we have decided to study the process of cerebellar fissuration. All brain MRI examinations performed in children for varied neurological and neurosurgical indications, especially children with non-specific mental retardation and patients with cerebral malformation detected at initial imaging work-up, were reviewed. Fissuration and lobulation anomalies (abnormal orientation of fissures, pseudopolymicrogyria, cortical thickening, subcortical cysts and heterotopia) were identified that we called cerebellar cortical dysplasia (CCD). In order to better understand the origin of this malformation, current data on cerebellar embryogenesis and histogenesis will be reviewed, and the pathological and radiological features will be illustrated. Milder forms of CCD represent a distinct group of anomalies that should be distinguished from other types of cerebellar dysplasia (agenesis, hypoplasia or complex dysplasia with involvement of the cerebellar vermis (rhombencephalosynapsis)) or combined cerebellar and cerebral dysplasia (muscular dystrophies and lissencephaly). Recognition of cerebellar cortical dysplasia could be a first step towards a broader understanding of its pathogenesis and significance.

Little documentation of the correlation between MR imaging findings in isolated cerebellar cortical dysplasia (CCD) and its neuropathologic characteristics exists in the recent literature. We documented a postmortem neuropathologic study of a clinically and radiologically well-documented case of CCD in a neonate with severe hypotonia and status epilepticus. MR imaging revealed a global vermian hypoplasia with marked cortical dysplasia. CCD was associated with a voluminous heterotopic mass. The postmortem neuropathologic study confirmed vermian hypoplasia and CCD, which consisted of right cerebellar cortical polymicrogyria with subcortical heterotopia. CCD is a pathologic entity that could be well diagnosed with MR imaging even in the neonatal period.

Several genes have been found to influence the different cells involved in the processes of foliation and fissuration in the mouse and rat cerebellum. In the light of these new concepts and on the basis of the imaging findings in 42 patients, a classification is proposed for abnormalities of foliation and fissuration. On the basis of recent genetic and experimental evidence on mechanisms which control the origin of the cerebellum, it is suggested that abnormalities of foliation and fissuration form a single group, with a spectrum of severity. Some patients have only abnormal fissuration of the anterior lobe (type 1a) and others additional dysplasia of the anterior and part of the posterior lobe (type 1b). Extension of abnormalities into the hemispheres is often seen in the latter group. A second group has vermian and hemisphere abnormalities (type 2). In addition to the malformation of the anterior lobe of the vermis, three different hemispheric lesions can be seen in this group: cortical dysgenesis, hypertrophy of the cerebellar cortex, and malorientation of the folia. The mild abnormalities (type 1a) can be considered an incidental observation without clinical relevance. The moderate and severe cerebellar anomalies (type 1b and 2) are always associated with cerebellar symptoms and/or signs.

1. The authors' goal was to compare the size and density of Purkinje cells in the cerebellum of subjects with and without autism. Blocks of cerebellum were dissected at autopsy from the brains of age, sex- and postmortem-intervaled (PMI) groups of autistic and normal control individuals (N = 5 per group). Frozen, unfixed blocks were sectioned and stained with 1% cresyl violet. 2. The linear, molecular, granular densities and cross-sectional area of Purkinje cells were measured using computer-assisted image analysis. The average cross-sectional areas of Purkinje cells of the patients with autism were smaller by 24% when compared to the normal subjects. Two of the five autistic subjects had mean Purkinje cell sizes that corresponded to greater than 50% reduction in size. There was a substantial effect size difference in Purkinje cell size (eta2 = 0.29) between control and autistic brains (F(1, 8) = 3.32, P = 0.106). No differences in Purkinje cell densities were observed between the two groups 3. These data indicate the possibility of Purkinje cell atrophy in autism with significant neurohistological heterogeneity among individuals diagnosed with this disorder.

To determine whether the neurogenetic patterns of Purkinje cells and deep cerebellar nuclei neurons were normal in weaver homozygotes and whether the degeneration of those neuronal types was linked to their time of origin, [3H] thymidine autoradiography was applied on sections of homozygous weaver mice and normal controls on postnatal day 90. The experimental animals were the offspring of pregnant dams injected with [3H] thymidine on embryonic days 11-12, 12-13, 13-14 and 14-15. The results show that the onset of neurogenesis, its pattern of peaks and valleys, and its total span were similar between wild type and homozygous weaver in the cerebellar areas analyzed, indicating that the loss of Purkinje cells and deep cerebellar nuclei neurons is not related to neurogenetic patterns. In weaver homozygotes, the loss of Purkinje cells and deep cerebellar nuclei neurons followed a lateral to medial gradient of increasing severity. Thus, the vermis and the fastigial nucleus, which are medially located, presented the most important neuron loss, whereas in the lateral hemisphere and the dentate nucleus, neuron loss was spared.

Mice that lack all beta1-class integrins in neurons and glia die prematurely after birth with severe brain malformations. Cortical hemispheres and cerebellar folia fuse, and cortical laminae are perturbed. These defects result from disorganization of the cortical marginal zone, where beta1-class integrins regulate glial endfeet anchorage, meningeal basement membrane remodeling, and formation of the Cajal-Retzius cell layer. Surprisingly, beta1-class integrins are not essential for neuron-glia interactions and neuronal migration during corticogenesis. The phenotype of the beta1-deficient mice resembles pathological changes observed in human cortical dysplasias, suggesting that defective integrin-mediated signal transduction contributes to the development of some of these diseases.

We describe MRI findings in two patients with disorganised foliation of one cerebellar hemisphere, with folia running vertically rather than horizontally. The thickness of individual folia and corticomedullary interdigitations were normal. These patients have no cerebellar neurological deficit. This rare abnormality is probably a maldevelopment of the hemispheric part of the posterior lobe of the developing cerebellum, and no clinical significance can be elicited.

Hotfoot is a mutant mouse with an ataxic phenotype which has been shown to be due to a mutation in the Grid2 gene. In this paper, we compare molecular, morphological, electrophysiological and behavioral features of two Grid2 alleles: Grid2(ho-4J) and Grid2(ho-Nancy). We first show that these two mutations are deletions in the open reading frame of the gene and that no GRID2 protein is detectable in extracts of mutant cerebella, suggesting that the two alleles are null-like mutations. Morphological and electrophysiological analyses reveal no obvious differences between the two strains: both strains showed the naked Purkinje dendritic spines and mismatch between the length of the presynaptic active zone and postsynaptic differentiation characteristic of the hotfoot mutation; and the same low level (20%) of multiple climbing fiber innervation of Purkinje cells was found in both strains. Only differences in motor behavior were found between the two strains. The Grid2(ho-4J) mouse shows more severe ataxia that the Grid2(ho-Nancy) mouse and, although both strains show a clear capacity to improve their performance of a motor task with training, the Grid2(ho-4J) performance remains very poor whereas Grid2(ho-Nancy) mice approach control levels. The only difference between the two strains is their genetic background. Our results show that the genetic background must be taken into account when analyzing sensorimotor performances of mutant mice.

Background and Purpose: MR imaging findings of cerebellar cortical dysplasia have been described as a new cerebellar malformation. The purpose of this study was to assess the association of cerebellar cortical dysplasia with other cerebral malformations., Methods: We retrospectively reviewed 46 MR examinations of patients presenting with developmental delay, hypotonia, and facial deformities to identify abnormal folia or fissures or both within cerebellar hemispheres or vermis suggesting cortical dysplasia., Results: Cerebellar cortical dysplasia was diagnosed in 17 patients. In two patients, it was isolated. In the remaining 15 patients, the malformation was associated with vermian malformation (n=11), cerebral cortical dysplasias (n=8), dysplasia of corpus callosum (n=6), and heterotopia (n=5). A widespread malformation of the posterior fossa was observed in eight patients (Dandy-Walker, Chiari II and III, and hypoplasia of brain stem). One patient with hypertrophied cerebellar hemisphere had minor enlargement of the right cerebral hemisphere and lateral ventricle. He also had nodular heterotopia, suggesting unilateral megalencephaly., Conclusion: Our study suggests that cerebellar cortical dysplasias are common in cases with more widespread cerebral malformations. Technical progress providing high-quality tridimensional MR imaging of the cerebellum may explain its recent descriptions.

The Snell dwarf mouse (Pit1dw-J homozygote) has a mutation in the Pit1 gene that prevents the normal formation of the anterior pituitary. In neonates and adults there is almost complete absence of growth hormone (GH), prolactin (PRL), thyroxin (T4), and thyroid-stimulating hormone (TSH). Since these hormones have been suggested to play a role in normal development of the central nervous system (CNS), we have investigated the effects of the Pit1dw-J mutation on the cerebellum and hippocampal formation. In the cerebellum, there were abnormalities of both foliation and lamination. The major foliation anomalies were 1) changes in the relative size of specific folia and also the proportional sizes of the anterior vs posterior cerebellum; and 2) the presence of between one and three microfolia per half cerebellum. The microfolia were all in the medial portion of the hemisphere in the caudal part of the cerebellum. Each microfolium was just rostral to a normal fissure and interposed between the fissure and a normal gyrus. Lamination abnormalities included an increase in the number of single ectopic granule cells in the molecular layer in both cerebellar vermis (86%) and hemisphere (40%) in comparison with the wild-type mouse. In the hippocampus of the Pit1dw-J homozygote mouse, the number of pyramidal cells was decreased, although the width of the pyramidal cell layer throughout areas CA1-CA3 appeared to be normal, but less densely populated than in the wild-type mouse. Moreover, the number of granule cells that form the granule cell layer was decreased from the wild-type mouse and some ectopic granule cells (occurring both as single cells and as small clusters) were observed in the innermost portion of the molecular layer. The abnormalities observed in the Pit1dw-J homozygote mouse seem to be caused by both direct and indirect effects of the deficiency of TSH (or T4), PRL, or GH rather than by a direct effect of the deletion of Pit1.

Lurcher mutant mice (+/Lc) exhibit a massive loss of neurons in the cerebellar cortex and the inferior olivary nucleus, while deep cerebellar nuclei are essentially intact. To discriminate the relative participation of the cerebellar cortex and deep structures in learning and memory, 3 to 6-month-old +/Lc mice were subjected to a spatial learning task derived from the Morris water escape. They were able to learn to escape as well as their strain-matched controls (+/+). Seven days later, their scores showed that they had memorized the spatial environment but not as accurately as +/+ mice. Cerebellectomy before training did not significantly alter the escape learning capabilities of either group, whereas cerebellectomy performed after learning completely abolished retention in +/+, as well as in +/Lc, mice. These results suggest that the cerebellum, although not necessary for learning a spatial task, plays a crucial role in its retention, and that the storing structure of spatial information differs in +/+ and +/Lc mice.

The malformation of focal pachypolymicrogyria might be the manifestation of an X-linked recessive disorder according to the results of this study. Three siblings revealed focal pachypolymicrogyria on magnetic resonance imaging (MRI) and had a strong family history of epilepsy and mental retardation. All three siblings had the same mother; the father of Patient 1 was not related to the mother, but the father of Patients 2 and 3 was related to her. The MRI of the father of Patients 2 and 3 demonstrated focal pachypolymicrogyria. The mother's MRI was normal. In this family, epilepsy or mental retardation was found mainly in the males (Patient 3 was an exception), and they were all born to female members of this family, not male. Patient 3 was probably a homozygote with an X-linked recessive inheritance, and therefore, she demonstrated the most severe clinical findings.

MR imaging findings are described in four patients with cerebellar cortical dysplasia. Typically, cerebellar disorganized folia were seen as an irregular bumpy gray-white matter interface. In addition, cystlike cortical abnormalities were observed in two patients and associated supratentorial developmental abnormalities were seen in three patients. To our knowledge, cerebellar cortical dysplasia without supratentorial abnormalities, as seen in one patient, has not been reported before. We suggest that cerebellar cortical dysplasia represents a spectrum of abnormalities ranging from mild to extensive in severity.

The reeler mutation in mice produces an especially well characterized disorder, with systematically abnormal migration of cerebral cortical neurons. The reeler gene encodes a large protein, termed Reelin, that in the cortex is synthesized and secreted exclusively in the Cajal-Retzius neurons of the cortical marginal zone (D'Arcangelo et al., 1995). In reeler mutant mice, loss of Reelin protein is associated with a systematic loss of the normal, "inside-out" sequence of neurogenesis in the cortex: neurons are formed in the normal sequence but become localized in the cortex in a somewhat inverted, although relatively disorganized "outside-in" pattern. Here we show that the scrambler mutant mouse exhibits a loss of lamination in the cortex and hippocampus that is indistinguishable from that seen in the reeler mouse. We use BrdU birthdating studies to show that scrambler cortex shows a somewhat inverted "outside-in" sequence of birthdates for cortical neurons that is similar to that previously described in reeler cortex. Finally, we perform staining with the CR-50 monoclonal antibody (Ogawa et al., 1995), which recognizes the Reelin protein (D'Arcangelo et al., 1997). We show that Reelin immunoreactivity is present in the scrambler cortex in a normal pattern, suggesting that Reelin is synthesized and released normally. Our data suggest that scrambler is a mutation in the same gene pathway as the reeler gene (Relnrl) and is most likely downstream of Relnrl.

Purpose: To determine characteristic MR imaging features of Zellweger syndrome., Methods: Clinical records, laboratory records, and MR studies of six patients with Zellweger syndrome were reviewed retrospectively. MR studies were examined for the state of myelination; the presence, extent, and morphologic appearance of cerebral cortical anomalies; the status of the cerebellar cortex, basal nuclei, and brain stem; and the presence or absence of any regions of abnormal signal intensity., Results: The diagnosis of Zellweger syndrome was established in all patients by clinical findings combined with laboratory and MR results. All patients had impaired myelination and diffusely abnormal cortical gyral patterns that consisted of regions of microgyria (primarily in the frontal and perisylvian cortex) together with regions of thickened pachygyric cortex (primarily perirolandic and occipital). The pachygyric regions were in the form of deep cortical infoldings. Germinolytic cysts were visible in the caudothalamic groove in all patients, seen best on coronal or sagittal T1-weighted images. One patient had T1 shortening in the bilateral globus pallidus, presumably related to hepatic dysfunction and hyperbilirubinemia., Conclusion: The combination of hypomyelination, cortical malformations that are most severe in the perisylvian and perirolandic regions, and germinolytic cysts are highly suggestive of Zellweger syndrome in the proper clinical setting.

Cerebellar deficient folia, cdf, is a spontaneous autosomal recessive mutation in the mouse with unique pathology; the cerebellar cortex of the cdf/cdf mouse has only 7 folia instead of 10, which is the normal count for the C3H/HeJ strain in which this mutation arose. The cerebellum of the cdf/cdf mouse is hypoplastic and contains mineral deposits in the ventral vermis that are not present in controls. We used an intersubspecific intercross between C3H/HeSnJ-cdf/+ and Mus musculus castaneus (CAST/Ei) to map the cdf mutation to Chromosome (Chr) 6. The most likely gene order is D6Mit16-(cdf, D6Mit3)-D6Mit70-D6Mit29-D6Mit32, which positions cdf distal to lurcher (Lc) and proximal to motor neuron degeneration 2 (mnd2). The definitive visible phenotypes and histopathologies of cdf, Lc, and mnd2 support our mapping evidence that cdf is a distinct gene. The novel pathology of cdf should help elucidate the complicated process of cerebellar folia patterning and development. cdf recombined with mouse atonal homolog 1, Math1, the mouse homolog of the Drosophila atonal gene.

It has been speculated that the cerebellar primitive neuroectodermal tumor (PNET) in part recapitulates stages in the maturation of normal human neuroblasts. One theory suggests that these tumors may arise from "primitive cells" or "remnants" of the external granular layer of the cerebellum, which forms a subpial, proliferative zone that gives rise to neurons of the internal granular layer and stellate and basket cells. In the present report, the coexistence of marked cerebellar cortical disorganization and cerebellar PNET is described in a 1-year-old boy. The abnormal dysplastic cortex was in close proximity as well as contiguous to the tumor. Although minor degrees of cerebellar dysplasia may be found incidentally, the coexistence of a severe malformative process contiguous to cerebellar PNET merits the consideration of a possible pathogenetic association between aberrant neuronal migration or maturation and the development of PNET in this patient.

A detailed neuropathological study of five immature brains with type II lissencephaly is reported. The cases described include two pairs of siblings. One infant survived for 2 months after birth, the others died at 18, 20, 20 and 32 weeks of gestation. This series of cases demonstrates the sequence in which the malformation develops from mid-gestation to post-natal life and shows that type II lissencephaly is not an intracortical malformation but is the result of massive glial and neuronal ectopia in the leptomeninges. This results from a failure of arrest of neuronal migration due to defects in the integrity of the pial/glial barrier.

The effect of ethanol on the cerebellar cortex of chick embryos was studied in semi-thin sections of material prepared for electron microscopy. The embryos were injected with ethanol on the 3rd or 6th day of incubation and observed until days 13, 15, 17 and 21 of development. A decrease was seen in the number of germinal cells generated, together with defects in neuronal migration and the existence of a lower quantity of cells due to a generalised process of cell death. At the same time, a progressive neuronal degeneration was observed until the 15th day of incubation, the tissue recovering progressively on days 17 and 21. On the other hand, the embryos treated with ethanol on the 3rd day were less affected than those injected on the 6th day.