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Anatomical connections are reported between the cerebellum and brainstem nuclei involved in swallow such as the nucleus tractus solitarius, nucleus ambiguus, and Kölliker-fuse nuclei. Despite these connections, a functional role of the cerebellum during swallow has not been elucidated. Therefore, we examined the effects of cerebellectomy on swallow muscle recruitment and swallow-breathing coordination in anesthetized freely breathing cats. Electromyograms were recorded from upper airway, pharyngeal, laryngeal, diaphragm, and chest wall muscles before and after complete cerebellectomy. Removal of the cerebellum reduced the excitability of swallow (i.e., swallow number), and muscle recruitment of the geniohyoid, thyroarytenoid, parasternal (chestwall), and diaphragm muscles, but did not disrupt swallow-breathing coordination. Additionally, diaphragm and parasternal muscle activity during swallow is reduced after cerebellectomy, while no changes were observed during breathing. These findings suggest the cerebellum modulates muscle excitability during recruitment, but not pattern or coordination of swallow with breathing., Author(s): Mitchell D. Reed [sup.1] , Mason English [sup.1] , Connor English [sup.1] , Alyssa Huff [sup.1] [sup.2] , Ivan Poliacek [sup.3] [sup.4] , M. Nicholas Musselwhite [sup.3] , Dena [...]

Persistent and ramping neural activity in the frontal cortex anticipates specific movements.sup.1-6. Preparatory activity is distributed across several brain regions.sup.7,8, but it is unclear which brain areas are involved and how this activity is mediated by multi-regional interactions. The cerebellum is thought to be primarily involved in the short-timescale control of movement.sup.9-12; however, roles for this structure in cognitive processes have also been proposed.sup.13-16. In humans, cerebellar damage can cause defects in planning and working memory.sup.13. Here we show that persistent representation of information in the frontal cortex during motor planning is dependent on the cerebellum. Mice performed a sensory discrimination task in which they used short-term memory to plan a future directional movement. A transient perturbation in the medial deep cerebellar nucleus (fastigial nucleus) disrupted subsequent correct responses without hampering movement execution. Preparatory activity was observed in both the frontal cortex and the cerebellar nuclei, seconds before the onset of movement. The silencing of frontal cortex activity abolished preparatory activity in the cerebellar nuclei, and fastigial activity was necessary to maintain cortical preparatory activity. Fastigial output selectively targeted the behaviourally relevant part of the frontal cortex through the thalamus, thus closing a cortico-cerebellar loop. Our results support the view that persistent neural dynamics during motor planning is maintained by neural circuits that span multiple brain regions.sup.17, and that cerebellar computations extend beyond online motor control.sup.13-15,18.The cerebellum is critical for the coding of future movement in the frontal cortex., Author(s): Zhenyu Gao [sup.1] , Courtney Davis [sup.2] , Alyse M. Thomas [sup.2] , Michael N. Economo [sup.3] , Amada M. Abrego [sup.2] , Karel Svoboda [sup.3] , Chris I. [...]

The position of the centrosome ahead of the nucleus has been considered crucial for coordinating neuronal migration in most developmental situations. The proximity of the centrosome has also been correlated with the site of axonogenesis in certain differentiating neurons. Despite these positive correlations, accumulating experimental findings appear to negate a universal role of the centrosome in determining where an axon forms, or in leading the migration of neurons. To further examine this controversy in an in vivo setting, we have generated cell type-specific multi-cistronic gene expression to monitor subcellular dynamics in the developing zebrafish cerebellum. We show that migration of rhombic lip-derived neurons is characterized by a centrosome that does not persistently lead the nucleus, but which is instead regularly overtaken by the nucleus. In addition, axonogenesis is initiated during the onset of neuronal migration and occurs independently of centrosome proximity. These in vivo data reveal a new temporal orchestration of organelle dynamics and provide important insights into the variation in intracellular processes during vertebrate brain differentiation. doi/ 10.1083/jcb.201004154

Cognitive functions show many alternative outcomes and great individual variation during normal aging. We examined learning over the adult life span in CBA mice, along with morphological and electrophysiological substrates. Our aim was to compare cerebellum-dependent delay eyeblink classical conditioning and hippocampus-dependent contextual fear conditioning in the same animals using the same conditioned and unconditioned stimuli for eyeblink and fear conditioning. In a subset of the behaviorally tested mice, we used unbiased stereology to estimate the total number of Purkinje neurons in cerebellar cortex and pyramidal neurons in the hippocampus. Several forms of synaptic plasticity were assessed at different ages in CBA mice: long-term depression (LTD) in both cerebellum and hippocampus and NMDA-mediated long-term potentiation (LTP) and voltage-dependent calcium channel LTP in hippocampus. Forty-four CBA mice tested at one of five ages (4, 8, 12, 18, or 24 months) demonstrated statistically significant age differences in cerebellum-dependent delay eyeblink conditioning, with 24-month mice showing impairment in comparison with younger mice. These same CBA mice showed no significant differences in contextual or cued fear conditioning. Stereology indicated significant loss of Purkinje neurons in the 18- and 24-month groups, whereas pyramidal neuron numbers were stable across age. Slice electrophysiology recorded from an additional 48 CBA mice indicated significant deficits in LTD appearing in cerebellum between 4 and 8 months, whereas 4- to 12-month mice demonstrated similar hippocampal LTD and LTP values. Our results demonstrate that processes of aging impact brain structures and associated behaviors differentially, with cerebellum showing earlier senescence than hippocampus. aging | cerebellum | hippocampus | behavior | synaptic plasticity doi/ 10.1073/pnas.0914207107

The comparative method is widely used to understand brain-behaviour relationships in comparative psychology. Such studies have demonstrated functional relationships between the brain and behaviour as well as how the brain and behaviour evolve in concert with one another. Here, the authors illustrate with their data on tool use and cerebellar morphology in birds that such comparisons can be further extended to (a) relate the morphology of a brain region to a behaviour, and (b) provide insight into the function of an often overlooked brain region in comparative cognitive studies, the cerebellum. Their results indicate that tool-using species have a significantly more folded cerebellar cortex, but not a larger cerebellum than non-tool-using species. This marks the first demonstration of an empirical relationship between the folding of a neural structure and a cognitive behaviour and in so doing, provides critical insight into the neural basis of tool use and the role of the cerebellum in cognitive processes. Keywords: tool use, cerebellum, comparative method, evolution, birds

Inactivation of homologous recombination (HR) or nonhomologous end-joining (NHEJ) predisposes to a spectrum of tumor types. Here, we inactivated DNA double-strand break repair (DSBR) proteins, DNA Ligase IV (Lig4), Xrcc2, and Brca2, or combined Lig4/ Xrcc2 during neural development using Nestin-cre. In all cases, inactivation of these repair factors, together with p53 loss, led to rapid medulloblastoma formation. Genomic analysis of these tumors showed recurring chromosome 13 alterations via chromosomal loss or translocations involving regions containing Ptch1. Sequence analysis of the remaining Ptch1 allele showed a variety of inactivating mutations in all tumors analyzed, highlighting the critical tumor suppressor function of this hedgehog-signaling regulator. We also observed genomic amplification or up-regulation of either N-Myc or cyclin D2 in all medulloblastomas. Additionally, chromosome 19, which contains Pten, was also selectively deleted in medulloblastoma arising after disruption of HR. Thus, our data highlight the preeminence of Ptch1 as a tumor suppressor in cerebellar granule cells and reveal other genomic events central to the genesis of medulloblastoma. DNA strand breaks | patched1 | sonic hedgehog | cerebellum

Despite the widespread distribution of inhibitory synapses throughout the central nervous system, plasticity of inhibitory synapses related to associative learning has never been reported. In the cerebellum, the neural correlate of fear memory is provided by a long-term potentiation (LTP) of the excitatory synapse between the parallel fibers (PFs) and the Purkinje cell (PC). In this article, we provide evidence that inhibitory synapses in the cerebellar cortex also are affected by fear conditioning. Whole-cell patch-clamp recordings of spontaneous and miniature GABAergic events onto the PC show that the frequency but not the amplitude of these events is significantly greater up to 24 h after the conditioning. Adequate levels of excitation and inhibition are required to maintain the temporal fidelity of a neuronal network. Such fidelity can be evaluated by determining the time window for multiple input coincidence detection. We found that, after fear learning, PCs are able to integrate excitatory inputs with greater probability within short delays, but the width of the whole window is unchanged. Therefore, excitatory LTP provides a more effective detection, and inhibitory potentiation serves to maintain the time resolution of the system. cerebellum | associative learning | GABA inhibition | Purkinje cells | fear

We report in this study that, in the cerebellum, the pancreatic transcription factor Ptf1a is required for the specific generation of Purkinje cells (PCs) and interneurons. Moreover, granule cell progenitors in the external GCL (EGL) appear to be unaffected by deletion of Ptf1a. Cell lineage analysis in [Ptf1a.sup.Cre/Cre] mice was used to establish that, in the absence of Ptf1a expression, ventricular zone progenitors, normally fated to produce PCs and interneurons, aberrantly migrate to the EGL and express typical markers of these cells, such as Math1, Reelin, and Zic1/2. Furthermore, these cells have a fine structure typical of EGL progenitors, indicating that they adopt an EGL-like cell phenotype. These findings indicate that Ptf1a is necessary for the specification and normal production of PCs and cerebellar interneurons. Moreover, our results suggest that Ptf1a is also required for the suppression of the granule cell specification program in cerebellar ventricular zone precursors. cerebellum | GABAergic cells | neural specification

The neuronal circuits of the cerebellar cortex are essential for motor and sensory learning, associative memory formation, and the vestibular ocular reflex. In children and young adults, tumors of the granule cell, the medulloblastomas, represent 40% of brain tumors. We report the differentiation of E14 ES cells into mature granule neurons by sequential treatment with secreted factors (WNT1, FGF8, and RA) that initiate patterning in the cerebellar region of the neural tube, bone morphogenic proteins (BMP6/7 and GDF7) that induce early granule cell progenitor markers (MATH1, MEIS1, ZIC1), mitogens (SHH, JAG1) that control proliferation and induce additional granule cell markers (Cyclin D2, PAX2/6), and culture in glial-conditioned medium to induce markers of mature granule neurons (GABA[[alpha].sub.6]r), including ZIC2, a unique marker for granule neurons. Differentiated ES cells formed classic 'T-shaped' granule cell axons in vitro, and implantation of differentiated Pde1c-Egfp-BAC transgenic ES cells into the external granule cell layer of neonatal mice resulted in the extension of parallel fibers, migration across the molecular layer, incorporation into the internal granule cell layer, and extension of short dendrites, typical of young granule cells forming synaptic connections with afferent mossy fibers. These results underscore the utility of treating ES cells with local, inductive signals that regulate CNS neuronal development in vivo as a strategy for cell replacement therapy of defined neuronal populations. cerebellum | CNS development | granule neuron | stem cell

The Sonic hedgehog (Shh) and FGF signaling pathways regulate growth and differentiation in many regions of the nervous system, but interactions between these pathways have not been studied extensively. Here, we examine the relationship between Shh and FGF signaling in granule cell precursors (GCPs), which are the most abundant neural progenitors in the cerebellum and the putative cell of origin for the childhood brain tumor medulloblastoma. In these cells, Shh induces a potent proliferative response that is abolished by coincubation with basic FGF. FGF also inhibits transcription of Shh target genes and prevents activation of a Gli-responsive promoter in fibroblasts, which suggests that it blocks Shh signaling upstream of Gli-mediated transcription. FGF-mediated inhibition of Shh responses requires activation of FGF receptors and of FRK and JNK kinases, because it can be blocked by inhibitors of these enzymes. Finally, FGF promotes differentiation of GCPs in vitro and in vivo and halts proliferation of tumor cells from patched (ptc) mutant mice, a model for medulloblastoma. These findings suggest that FGF is a potent inhibitor of Shh signaling and may be a useful therapy for tumors involving activation of the hedgehog pathway. brain tumor | cerebellum | FGF | medulloblastoma

The exchange factor directly activated by cAMP (Epac) is a newly discovered direct target for cAMP and a guanine-nucleotide exchange factor for the small GTPase Rap. Little is known about the neuronal functions of Epac. Here we show that activation of Epac by specific cAMP analogs or by the pituitary adenylate cyclase-activating polypeptide induces a potent activation of the [Ca.sup.2+]-sensitive big [K.sup.+] channel, slight membrane hyperpolarization, and increased after-hyperpolarization in cultured cerebellar granule cells. These effects involve activation of Rap and p38 MAPK, which mobilizes intracellular [Ca.sup.2+] stores. These findings reveal a cAMP Epac-dependent and protein kinase A-independent signaling cascade that controls neuronal excitability. excitability | granule cells | mouse | calcium | PACAP

Transmitter release at chemical synapses is triggered by high calcium concentration microprofiles at the presynaptic cytosol. Such microprofiles, generated by the opening of voltage-dependent calcium channels at the presynaptic plasma membrane, have been defined as calcium concentration microdomains. Using total internal reflection fluorescent microscopy in conjunction with calcium and vesicular release indicator dyes, we have directly visualized the close apposition of calcium concentration microdomains and synaptic release sites at single synaptic terminals from the CNS from rat cerebellar mossy fiber and squid optic lobe. These findings demonstrate the close apposition of calcium entry and release sites and the dynamics of such site locations over time. Kinetic analysis shows that vesicles can be released via two distinct mechanisms: full-fusion and kiss-and-run. Calcium triggers vesicular motion toward the membrane, and the speed of such movement is calcium concentration-dependent. Moreover, the immediately available vesicular pool represents molecularly trapped vesicles that can be located at a larger distance from the plasma membrane than the field illuminated by total internal reflection fluorescent microscopy. cerebellum | mossy fibers | squid | synaptic vesicles

Neural stem cells and progenitors in the developing brain must choose between proliferation with renewal and differentiation. Defects in navigating this choice can result in malformations or cancers, but the genetic mechanisms that shape this choice are not fully understood. We show by positional cloning that the 30-zinc finger transcription factor Zfp423 (OAZ) is required for patterning the development of neuronal and glial precursors in the developing brain, particularly in midline structures. Mutation of Zfp423 results in loss of the corpus callosum, reduction of hippocampus, and a malformation of the cerebellum reminiscent of human Dandy-Walker patients. Within the cerebellum, Zfp423 is expressed in both ventricular and external germinal zones. Loss of Zfp423 results in diminished proliferation by granule cell precursors in the external germinal layer, especially near the midline, and abnormal differentiation and migration of ventricular zone-derived neurons and Bergmann gila. choroidplexus Ebf1 | nur12 Roaz | SMADs

Delineating longitudinal relationships between early developmental markers, adult cognitive function, and adult brain structure could clarify the pathogenesis of neurodevelopmental disorders such as schizophrenia. We aimed to identify brain structural correlates of infant motor development (IMD) and adult executive function in nonpsychotic adults and to test for abnormal associations between these measures in people with schizophrenia. Representative samples of nonpsychotic adults (n = 93) and people with schizophrenia (n = 49) were drawn from the Northern Finland 1966 general population birth cohort. IMD was prospectively assessed at age 1 year; executive function testing and MRI were completed at age 33-35 years. We found that earlier motor development in infancy was correlated with superior executive function in nonpsychotic subjects. Earlier motor development was also normally associated with increased gray matter density in adult premotor cortex, striatum, and cerebellum and increased white matter density in frontal and parietal lobes. Adult executive function was normally associated with increased gray matter density in a fronto-cerebellar system that partially overlapped, but was not identical to, the gray matter regions normally associated with IMD. People with schizophrenia had relatively delayed IMD and impaired adult executive function in adulthood. Furthermore, they demonstrated no normative associations between fronto-cerebellar structure, IMD, or executive function. We conclude that frontal cortico-cerebellar systems correlated with adult executive function are anatomically related to systems associated with normal infant motor development. Disruption of this anatomical system may underlie both the early developmental and adult cognitive abnormalities in schizophrenia. neuroimaging | neurodevelopmental | connectivity | epidemiology | dysmetria

To purchase or authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1552-6569.2006.00034.x Byline: David H. Lewis (1), Judith P. Bluestone (1), Maryann Savina (1), William H. Zoller (1), Emily B. Meshberg (1), Satoshi Minoshima (1) Keywords: Cerebral perfusion SPECT; traumatic brain injury Abstract: ABSTRACT People in chronic phase of traumatic brain injury (TBI) are often told that there will be no further recovery in brain function that they are in a 'static phase.' Holistic Approach to NeuroDevelopment and Learning Efficiency (HANDLE[R]), an alternative therapy, aims to improve function by teaching a series of physical and mental activities that clients perform and encouraging changes in lifestyle. Five subjects (3 males) with chronic TBI (at least 3 years since ictus) completed the HANDLE Institute's program and were prospectively evaluated. Each had six regional cerebral blood flow (rCBF) single-photon emission computed tomography (SPECT) scans over 7 months (scans n= 30). Paired scans were performed with injection of Tc-99m ECD to image rCBF at rest and during the HANDLE 'Crossed Arm Bounce' (CAB) exercise before the program, at 3-4 months into the program, and at 6-7 months, after the program had ended. SPECT images were analyzed statistically using Neurostat in which image sets were coregistered and warped into Talaraich atlas for pairwise subtraction between conditions. Group analysis of SPECT showed that CAB activated (increased rCBF) vermis and cerebellar hemispheres in first two paired scans and anterior cingulate and vermis on the final pair. Increased rCBF at rest occurred in cerebellar hemispheres, vermis, and right dorsomedial frontal cortex. These preliminary observations suggest that there may be a role of the hindbrain (vermis and cerebellum) with HANDLE treatment of chronic TBI. Author Affiliation: (1)From the Harborview Medical Center, Division of Nuclear Medicine, Department of Radiology, University of Washington School of Medicine (DHL, EBM, SM); Department of Chemistry, University of Washington, Seattle, Washington (WHZ); and The HANDLE Institute, Seattle, Washington (JPB, MS). Article History: Received August 23, 2005, and in revised form January 5, 2006. Accepted for publication January 9, 2006. Article note: Address correspondence to David H. Lewis, Director, Nuclear Medicine, Harborview Medical Center, Associate Professor, Department of Radiology, 325 Ninth Avenue, 359772, Seattle, WA 98104. E-mail: lewis@u.washington.edu.

The maintenance of synaptic functions is essential for neuronal information processing, but cellular mechanisms that maintain synapses in the adult brain are not well understood. Here, we report an activity-dependent maintenance mechanism of parallel fiber (PF)-Purkinje cell (PC) synapses in the cerebellum. When postsynaptic metabotropic glutamate receptor (mGluR) or inositol 1,4,5-trisphosphate (IP3) signaling was chronically inhibited in vivo, PF-PC synaptic strength decreased because of a decreased transmitter release probability. The same effects were observed when PF activity was inhibited in vivo by the suppression of NMDA receptor-mediated inputs to granule cells. PF-PC synaptic strength similarly decreased after the in vivo application of an antibody against brain-derived neurotrophic factor (BDNF). Furthermore, the weakening of synaptic connection caused by the blockade of mGluR-[IP.sub.3] signaling was reversed by the in vivo application of BDNF. These results indicate that a signaling cascade comprising PF activity, postsynaptic mGluR-[IP.sub.3] signaling and subsequent BDNF signaling maintains presynaptic functions in the mature cerebellum. adult mouse | cerebellum | metabotropic glutamate receptor | neuronal activity | retrograde signaling

T-type calcium channels are thought to transform neuronal output to a burst mode by generating low voltage-activated (LVA) calcium currents and rebound burst discharge. In this study we assess the expression pattern of the three different T-type channel isoforms ([Ca.sub.v]3.1, [Ca.sub.v]3.2, and [Ca.sub.v]3.3) in cerebellar neurons and focus on their potential role in generating LVA spikes and rebound discharge in deep cerebellar nuclear (DCN) neurons. We detected expression of one or more Car3 channel isoforms in a wide range of cerebellar neurons and selective expression of different isoforms in DCN cells. We further identify two classes of large-diameter DCN neurons that exhibit either a strong or weak capability for rebound discharge, despite the ability to generate LVA spikes when calcium currents are pharmacologically isolated. By correlating the [Ca.sub.v]3 channel expression pattern with the electrophysiological profile of identified DCN cells, we show that [Ca.sub.v]3.1 channels are expressed in isolation in DCN-burst cells, whereas [Ca.sub.v]3.3 is expressed in DCN-weak burst cells. [Ca.sub.v]3.1-expressing DCN cells correspond to excitatory or GABAergic neurons, whereas [Ca.sub.v]3.3-expressing cells are non-GABAergic. The [Ca.sub.v]3 class of LVA calcium channels is thus expressed in specific combinations in a wide range of cerebellar neurons but contributes to rebound burst discharge in only a select number of cell classes. Purkinje cells | cerebellum | rebound discharge

Episodic ataxia type 2 (EA2) is an inherited autosomal dominant disorder related to cerebellar dysfunction and is associated with mutations in the pore-forming [[alpha].sub.1A]-subunits of human P/Q-type [Ca.sup.2+] channels (Cav2.1 channels). The majority of EA2 mutations result in significant loss-of-function phenotypes. Whether EA2 mutants may display dominant-negative effects in human, however, remains controversial. To address this issue, five EA2 mutants in the long isoform of human [[alpha].sub.1A]-subunits were expressed in Xenopus oocytes to explore their potential dominant-negative effects. Upon coexpressing the cRNA of [[alpha].sub.1A]-WT with each [[alpha].sub.1A]-mutant in molar ratios ranging from 1:1 to 1:10, the amplitude of [Ba.sup.2+] currents through wild-type (WT)-Cav2.1 channels decreased significantly as the relative molar ratio of [[alpha].sub.1A]-mutants increased, suggesting the presence of an [[alpha].sub.1A]-mutant-specific suppression effect. When we coexpressed [[alpha].sub.1A]-WT with proteins not known to interact with Cav2.1 channels, we observed no significant suppression effects. Furthermore, increasing the amount of auxiliary subunits resulted in partial reversal of the suppression effects in nonsense but not missense EA2 mutants. On the other hand, when we repeated the same coinjection experiments of [[alpha].sub.1A]-WT and mutant using a splice variant of [[alpha].sub.1A]-subunit that contained a considerably shorter COOH terminus (i.e., the short isoform), no significant dominant-negative effects were noted until we enhanced the relative molar ratio to 1:10. Altogether, these results indicate that for human WT-Cav2.1 channels comprising the long-[[alpha].sub.1A]-subunit isoform, both missense and nonsense EA2 mutants indeed display prominent dominant-negative effects. channelopathy; voltage clamp: Xenopus oocytes; cerebellum; splice variants

The cerebellum is known to be critical for accurate adaptive control and motor learning. We propose here a mechanism by which the cerebellum may replace reflex control with predictive control. This mechanism is embedded in a learning rule (the delayed eligibility trace rule) in which synapses onto a Purkinje cell or onto a cell in the deep cerebellar nuclei become eligible for plasticity only after a fixed delay from the onset of suprathreshold presynaptic activity. To investigate the proposal that the cerebellum is a general-purpose predictive controller guided by a delayed eligibility trace rule, a computer model based on the anatomy and dynamics of the cerebellum was constructed. It contained components simulating cerebellar cortex and deep cerebellar nuclei, and it received input from a middle temporal visual area and the inferior olive. The model was incorporated in a real-world brain-based device (BBD) built on a Segway robotic platform that learned to traverse curved paths. The BBD learned which visual motion cues predicted impending collisions and used this experience to avoid path boundaries. During learning, the BBD adapted its velocity and turning rate to successfully traverse various curved paths. By examining neuronal activity and synaptic changes during this behavior, we found that the cerebellar circuit selectively responded to motion cues in specific receptive fields of simulated middle temporal visual areas. The system described here prompts several hypotheses about the relationship between perception and motor control and may be useful in the development of general-purpose motor learning systems for machines. cerebellum | computational model | eligibility trace | middle temporal visual area

Effects of BETA2/neurogenic differentiation 1 expression on development of anterior and posterior parts of cerebellum are presented.

Efficient clearance of synaptically released glutamate from the extracellular space is an absolute requirement for maintaining information processing in the central nervous system. In the cerebellum, clearance of glutamate relies on uptake by Bergmann glial cells and Purkinje cells (PCs). Uptake by PCs can be monitored by recording the synaptic transport current (STC) mediated by the PC-specific transporter excitatory amino acid transporter 4 (EAAT4). The slow time course of the PC STC has been used to argue that glutamate clearance is protracted. We find, however, that the time course of the STC is not affected by altering the amount of glutamate released at individual synapses or by partial transporter blockade, manipulations that would be expected to change the duration of the extracellular glutamate transient. Ion substitution experiments and kinetic modeling of the PC transporter current suggest that physiological levels of intracellular [Na.sup.+] and glutamate slow the cycling rate of transporters and thereby lengthen the time course of STCs. The model predicts that PC transporters bind glutamate quickly but that the actual cycling rate of EAAT4 in physiological conditions is slow; therefore, the STC reflects the intrinsic kinetics of the glutamate transporter, not the rate of glutamate clearance. cerebellum | climbing fiber | parallel fiber | Purkinje

Long-term potentiation (LTP) is mediated by the activity-driven delivery of GluR1 glutamate receptors via [Ca.sup.2+]/ calmodulin-dependent protein kinase II activity in various brain regions. Recently, postsynaptic LTP was shown to be induced at parallel fiber-Purkinje cell synapses by stimulating the parallel fibers at 1 Hz or applying a NO donor. Here, we demonstrate that NO-evoked postsynaptic LTP in mice cerebellum was blocked by botulinum toxin and enhanced by prior treatment with phorbol ester, which is known to induce GluR2 endocytosis. Interestingly, such LTP was not affected by a [Ca.sup.2+]/calmodulin-dependent protein kinase II inhibitor or a peptide binding to a protein interacting with C kinase 1, but was blocked by a peptide binding to N-ethylmaleimide-sensitive factor, which specifically binds to GluR2. Therefore, although the synaptic incorporation of GluR2 has been reported to be a constitutive pathway, NO-induced postsynaptic LTP in Purkinje cells is likely mediated by a pathway involving N-ethylmaleimide-sensitive factor-dependent GluR2 trafficking. cerebellum | glutamate receptor | long-term depression | nitric oxide

Memories are believed to be encoded by changes in the synaptic connections between neurons. Although many forms of synaptic plasticity have been identified, it remains unknown how such changes affect local circuits. Feedforward inhibitory networks are a common type of local circuitry and occur when principal neurons and their afferent inhibitory interneurons receive the same input. Using slices of cerebellar cortex, we explored how synaptic plasticity at multiple sites within a feedforward inhibitory network consisting of parallel fibers, interneurons, and Purkinje neurons alters the output of this circuit. We found that stimuli resembling baseline activity potentiated feedforward excitatory and simultaneously depressed feedforward inhibitory pathways. In contrast, stimuli resembling sensory-evoked patterns of firing potentiated both types of feedforward connections. These distinct forms of ensemble plasticity change the way Purkinje neurons subsequently respond to inputs. Such concerted changes in the circuitry of cerebellar cortex may contribute to certain forms of sensorimotor learning. cerebellum | inhibition | interneuron | Purkinje

The function and origin of NG2+ cells in the adult brain are still controversial. A large amount of data is available which strongly indicates that adult NG2-expressing cells form a heterogeneous population, constituted by oligodendrocyte precursor cells (OPCs) and a fourth novel type of glial cells named the synantocytes. Whether these two populations derive from the progressive maturation of perinatal NG2+ OPCs or are generated as separate populations is not known. We used organotypic cultures of newborn mouse cerebellum depleted, by anti-mitotic drug treatment, of their NG2+ cells with perinatal features (high proliferating rate and high oligodendrocytic differentiation ability). In these cultures, despite the lack of myelin after 14 days in vitro, numerous NG2+ cells remained. We show that these BrdU-resistant cells were able to slowly divide, as adult NG2+ cells do. Although many of these cells expressed 04, only a very small fraction of them was further engaged in oligodendrocyte lineage, as they had an extremely poor capacity to generate myelin sheaths to the Purkinje cell axons. These results support the view that at least two distinct populations of NG2+ cells coexist in the cerebellum from birth: one with the young OPC characteristics, another with adult NG2+ cell characteristics. Thus, a fraction of adult NG2+ cells do not derive from the maturation of perinatal OPCs. Keywords: Oligodendrocyte depletion; NG2; Oligodendrocyte precursor cell; Myelination; Proliferation; Migration; Cerebellum

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. autism | cerebellum | communication | language | speech

Contemporary mechanistic models of several psychiatric disorders propose abnormalities in the structure and function of distinct neural networks. The cerebellum has both anatomic and functional connections to the prefrontal cortex, [...]

Primary culture of postnatal cerebellar granule cells provides a model system that recapitulates many molecular events of developing granule cells in vivo. Depolarization of cultured granule cells increases intracellular [Ca.sup.2+] and activates [Ca.sup.2+]/calmodulindependent calcineurin (CAN) phosphatase. This [Ca.sup.2+] signaling mimics some of the signaling events for proliferation, migration, and differentiation of granule cellsin vivo. We investigated the genome-wide expression profiles of depolarization- and CaN-regulated genes in cultured mouse granule cells and addressed their relevance to gene regulation in developing granule cells in vivo. Granule cells were cultured under a nondepolarization condition (5 mM KCI) and a depolarization condition (25 mM KCI) with and without the CaN inhibitor FKS06. Gene expression profiles between depolarization and nondepolarization and between FK506 treatment and untreatment were analyzed by microarray techniques. Both depolarization and FKS06 treatment influence expression levels of a large number of genes, most of which are overlapping, however, are conversely regulated by these two treatments. Importantly, many of the FK506-responsive genes are up- or down-regulated in parallel with gene expression in postnatal granule cells in vivo. The FK506-down-regulated genes are highly expressed in proliferating/premigratory granule cells and many of these genes encode cellular components involved in cell proliferation, migration, and differentiation. In contrast, the FK506-up-regulated genes are predominantly expressed in post-migratory granule cells, including many functional molecules implicated in synaptic transmission and modulation. This investigation demonstrates that the CaN signaling plays a pivotal role in development and synaptic organization of granule cells during the postnatal period. calcium signaling | cell culture | cerebellum | gene expression | microarray

Byline: A. Ozimek (1), S. Richter (1), C. Hein--Kropp (1), B. Schoch (2), B. Gorissen (1), O. Kaiser (1), E. Gizewski (3), W. Ziegler (4), D. Timmann (1) Keywords: cerebellum; children; dysarthria; posterior fossa syndrome Abstract: Abstract. The aim of the present study was to investigate the manifestations of mutism after surgery in children with cerebellar tumors. Speech impairment following cerebellar mutism in children was investigated based on standardized acoustic speech parameters and perceptual criteria. Mutistic and non--mutistic children after cerebellar surgery as well as orthopedic controls were tested pre--and postoperatively. Speech impairment was compared with the localization of cerebellar lesions (i. e. affected lobules and nuclei). Whereas both control groups showed no abnormalities in speech and behavior, the mutistic group could be divided into children with dysarthria in post mutistic phase and children with mainly behavioral disturbances. In the mutistic children involvement of dentate and fastigial nuclei tended to be more frequent and extended than in the nonmutistic cerebellar children. Cerebellar mutism is a complex phenomenon of at least two types. Dysarthric symptoms during resolution of mutism support the anarthria hypothesis, while mainly behavioral changes suggest an explanation independent from speech motor control. Author Affiliation: (1) Dept. of Neurology, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany (2) Dept. of Neurosurgery, University of Duisburg-Essen, Essen, Germany (3) Dept. of Neuroradiology, University of Duisburg-Essen, Essen, Germany (4) EKN -- Clinical Neuropsychology Research Group, Dept. of Neuropsychology City Hospital Bogenhausen, Munich, Germany Article History: Registration Date: 01/01/2004 Received Date: 06/10/2003 Accepted Date: 12/03/2004

Byline: A. B. Melik-Musyan (1), V. V. Fanardzhyan (1) Keywords: cerebellar cortex; neurons; interneuronal connections; Lugaro cells Abstract: Two types of Lugaro cells were identified in the cat cerebellar cortex using sections impregnated with silver nitrate by the Golgi-Kopsch method these cells were fusiform and triangular and their bodies were located at different levels in the granular layer. Their processes were directed horizontally, vertically, or obliquely to the axis of the leaf axons never left the cerebellar cortex. These cells should therefore be regarded as interneurons. The processes of Lugaro cells were very extended, with the result that these cells formed numerous axosomatic and axodendritic contacts with all cerebellar cortical neurons and fibers. The structural and topographical characteristics of Lugaro cells and the features of their contacts with other cells in the cerebellar cortex, taken together with data on their neurotransmitter contents, show that they function as inhibitory interneurons. Author Affiliation: (1) Central Nervous System Physiology Laboratory, L. A. Orbeli Institute of Physiology, Armenian National Academy of Sciences, Erevan Article History: Registration Date: 18/10/2004

Byline: Matthias Maschke (3), Johannes Weber (1), Albena Dimitrova (3), Udo Bonnet (2), Julia Bohrenkamper (3), Sonja Sturm (3), Kerstin Kindsvater (1), Bernhard W. Muller (2), Markus Gastpar (2), Hans-Christoph Diener (3), Michael Forsting (1), Dagmar Timmann (3) Keywords: cerebellum; brain iron concentration; FLASH sequence; interrater reliability Abstract: Abstract. The aim of the present study was to investigate age-related changes in iron-deposition in dentate nuclei using iron-induced susceptibility effects in magnetic resonance imaging. MR images from 74 healthy subjects (age range 20--68 years) were obtained using a three-dimensional (3D) T1-weighted fast low angle shot (FLASH) echo sequence. Signal intensities of the dentate nuclei and cerebellar white matter were bilaterally measured independently by three blinded investigators. The signal intensities of dentate nuclei were intraindividually normalised to the corresponding signal intensities of the cerebellar white matter of corresponding slices. Mean normalised signal intensities were correlated with age and compared between different age decades and gender. Intraclass correlation coefficients were high (dentate nuclei: 0.98, cerebellar white matter: 0.75) indicating sufficient interrater reliabilities for the determination of signal intensities. Bland-Altman analysis confirmed this finding. The normalised mean signal intensity of the dentate nuclei correlated inversely with age (r = --0.462, p &lt 0.0001). Comparison of age decades revealed that significant decreases took place between the third and fourth decade and to a lesser degree between the fourth and fifth decade. Moreover, variability of normalised mean signal intensities of the dentate nuclei increased significantly with age (r = 0.964, p = 0.008). There were no differences of the normalised mean signal intensities between genders. The present study revealed an agedependent decrease of signal intensities in dentate nuclei most likely reflecting an age-dependent increase in dentate iron concentration. These age-dependent changes have to be taken into account in interpretation of disease related MR changes of cerebellar nuclei in patients with degenerative or acquired cerebellar ataxia. Author Affiliation: (1) Department of Neuroradiology, University of Duisburg-Essen, Hufelandstr. 55, Essen, Essen, Germany (2) Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, Virchowstr. 174, 45147, Essen, Germany (3) Department of Neurology, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany Article History: Registration Date: 01/01/2004 Received Date: 28/04/2003 Accepted Date: 30/01/2004

We have studied the temporal and spatial control of cell migration from the external germinal layer (EGL) in the mammalian cerebellum as a model for cortical migration. Our results have demonstrated that embryonic EGL cells do not migrate into internal layers because they respond to a diffusible attractant in the meninges, the nonneural tissues covering the nervous system, and to a repellent in the neuroepithelium. Two developmental changes are important for postnatal EGL migration: the disappearance of the repellent in the inner layers and a switch in cellular responsiveness of EGL cells so that the postnatal EGL cells respond to the repellent, but not the attractant in the meninges. Besides revealing the signaling role of meninges in cortical development, our study suggests that an active mechanism is required to prevent cell migration, and that mechanisms of cell migration should be studied even in the absence of apparent changes in cell positions. We propose a model for the developmental control of neuronal migration in the cerebellar cortex. Keywords: Cell migration; Neuronal migration; Cortex; Cerebellum; Neural development

Byline: C. Globas (1), S. Bosch (2), Ch. Zuhlke (3), I. Daum (4), J. Dichgans (1), K. Burk (1) Keywords: Spinocerebellar ataxia; autosomal-dominant cerebellar ataxia; cerebellum; cognition; SCA6 Abstract: Abstract. The aim of this study was to assess cognitive function in patients with spinocerebellar ataxia type 6 (SCA6), an autosomal-dominantly inherited disease leading to a progressive cerebellar syndrome. In contrast to other SCA types, the pathological changes are mostly restricted to the cerebellum. Cognitive function was studied in 12 patients with genetically confirmed SCA6 (mean duration of disease: 9.2 +- 11.6 years) and 12 age- and IQ-matched controls using a test battery comprising tests for IQ, attention, verbal and visuospatial memory, as well as executive function. While none of the SCA6 subjects had features of general intellectual impairment, only mild deficits in single subtests especially in fronto-executive tasks were observed, but without reaching statistical significance. Thus the current findings do not demonstrate severe cognitive dysfunction in SCA6. Author Affiliation: (1) Department of Neurology, University of Tubingen, Hoppe-Seyler-Str. 3, 72076, Tubingen, Germany (2) Department of Neurology, University of Innsbruck, Austria (3) Department of Human Genetics, University of Lubeck, Germany (4) Department of Clinical Neuropsychology, University of Bochum, Germany Article History: Registration Date: 01/01/2003 Received Date: 13/02/2003 Accepted Date: 19/08/2003

Medulloblastoma is a cerebellar tumor that can arise through aberrant activation of Sonic hedgehog (Shh) signaling, which normally regulates cerebellar granule cell proliferation. Mutations of the Shh receptor PATCHED (PTCH) are associated with medulloblastomas, which have not been found to have loss of PTCH heterozygosity. We address whether patched (Ptc) heterozygosity fundamentally alters granule cell differentiation and contributes to tumorigenesis by increasing proliferation and/or decreasing apoptosis in Ptc mice. Our data show that postnatal Ptc mouse granule cell precursor growth is not globally altered. However, many older Ptc mice display abnormal cerebellar regions containing persistently proliferating granule cell precursors. Since fewer Ptc mice form medulloblastomas, these granule cell rests represent a developmentally disrupted, but uncommitted stage of tumorigenesis. Although Ptc mouse medulloblastomas express neurodevelopmental genes, they diverge from granule cell differentiation in their discordant coexpression of postmitotic markers despite their ongoing growth. Like human medulloblastomas, mouse tumors with reduced levels of the neurotrophin-3 receptor, trkC/Ntrk3, display decreased apoptosis in vivo, illustrating the role of TrkC in regulating tumor cell survival. These results indicate that Ptc heterozygosity contributes to tumorigenesis by predisposing a subset of granule cell precursors to the formation of proliferative rests and subsequent dysregulation of developmental gene expression. Keywords: Apoptosis; Cerebellum; Granule cell; Medulloblastoma; Mouse; patched; Proliferation; trkC

Byline: H. J. Donkelaar (1), M. Lammens (1,2), P. Wesseling (2), H. O. Thijssen (3), W. O. Renier (1,4) Keywords: cerebellum; rhombic lip; development; congenital malformations; Dandy-Walker malformation; pontocerebellar hypoplasias Abstract: The human cerebellum develops over a long time, extending from the early embryonic period until the first postnatal years. This protracted development makes the cerebellum vulnerable to a broad spectrum of developmental disorders. The development of the cerebellum occurs in four basic steps: 1) characterization of the cerebellar territory at the midbrain-hindbrain boundary 2) formation of two compartments for cell proliferation: first, the Purkinje cells and the deep cerebellar nuclei arise from the ventricular zone of the metencephalic alar plate second, granule cell precursors are formed from a second compartment of proliferation, i. e. the upper rhombic lip 3) inward migration of the granule cells: granule precursor cells form the external granular layer, from which (and continuing into the first postnatal year), granule cells migrate inwards to their definite position in the internal granular layer, and 4) formation of cerebellar circuitry and further differentiation. The precerebellar nuclei, i. e. the pontine nuclei and the inferior olive, arise from the lower rhombic lip. Developmental disorders of the cerebellum are often accompanied by malformations of the precerebellar nuclei. In this review the development of the cerebellum and some of its more frequent developmental disorders, such as the Dandy-Walker and related midline malformations, and the pontocerebellar hypoplasias, are discussed. Author Affiliation: (1) 321 Dept. of Neurology, University Medical Centre Nijmegen, 9101, 6500 HB, Nijmegen, The Netherlands (2) Dept. of Pathology, University Medical Centre Nijmegen, Nijmegen, The Netherlands (3) Dept. of Radiology, University Medical Centre Nijmegen, Nijmegen, The Netherlands (4) Dept. of Pediatric Neurology, University Medical Centre Nijmegen, Nijmegen, The Netherlands Article History: Received Date: 21/02/2003 Accepted Date: 01/07/2003

Neurogenesis in the cerebellum proceeds through a temporal series of cell production from two separate epithelia, the ventricular zone (VZ) and the external granule cell layer (EGL). Using the laacZ cell lineage tracer in transgenic mice, we describe cellular clones whose dates of birth span the entire period of cerebellar development and deduce a sequence of cell dispersion leading to the final allocation of cells in the cerebellum. Clones probably labeled early during neural tube formation show that individual progenitors can give rise to all cerebellar cell types. The distribution of clonally related granule cells in these clones indicates a mediolateral organization of EGL progenitors already established before the allocation of the EGL progenitors to the cerebellum. Clones restricted to the cerebellar VZ show that the VZ derives progenitors for deep nuclei and multipotent cortical progenitors, which lose their systematic lineage relationship when longitudinal cell intermingling in the cerebellar VZ becomes more limited. The small clones also show that cell dispersion is radial in the internal granule layer and tangential in the molecular layer. Together, the data demonstrate the broad maintenance of the relative order of cells from neural tube stages to the adult cerebellum. Keywords: Cell lineage: Cerebellum: Clonal analysis; Deep nuclei; laacZ; Mouse embryo; Neurogenesis

During development, inferior olivary axons cross the floor plate and project from the caudal to the rostral hindbrain, whence they grow into the cerebellar plate. We have investigated the axon guidance signals involved in the formation of this projection in vitro. When the cerebellar plate was grafted ectopically along the margin of the hindbrain in organotypic cultures, inferior olivary axons could pathfind to the ectopic cerebellum, establishing a topographically normal projection. Following rostrocaudal reversal of a region of tissue in the axon pathway between the inferior olive and the cerebellum, olivary axons still navigated towards the cerebellum. Moreover, olivary axons could cross a bridging tissue explant (spinal cord) to reach a cerebellar explant. In collagen gel cultures of inferior olive explants, olivary axon outgrowth increased significantly in the presence of cerebellar explants and axons deflected towards the cerebellar tissue. These results show that the cerebellum is a source of diffusible axon guidance signals for olivary axons. We also found that, in organotypic cultures, olivary axons which had crossed the floor plate showed an increased tendency to respond to cerebellar cues. Taken together, these results indicate that the cerebellum is the source of cues that are chemoattractant and growth-promoting for interior olivary axons; prior exposure to the floor plate increases responsiveness to these cues. Keywords: Inferior olive; Climbing fibres; Cerebellum; Hindbrain; Floor plate; Axon guidance; Chemoattraction