Royal Dutch Academy of Arts and science

Amsterdam, Netherlands

Royal Dutch Academy of Arts and science

Amsterdam, Netherlands
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Mark M.D.,Ruhr University Bochum | Krause M.,Ruhr University Bochum | Boele H.-J.,Erasmus Medical Center | Kruse W.,Ruhr University Bochum | And 7 more authors.
Journal of Neuroscience | Year: 2015

Spinocerebellar ataxia type 6 (SCA6) is linked to poly-glutamine (polyQ) within the C terminus (CT) of the pore-forming subunits of P/Q-type Ca2+ channels (Cav2.1) and is characterized by CT protein aggregates found in cerebellar Purkinje cells (PCs). One hypothesis regarding SCA6 disease is that a CT fragment of the Cav2.1 channel, which is detected specifically in cytosolic and nuclear fractions in SCA6 patients, is associated with the SCA6 pathogenesis. To test this hypothesis, we expressed P/Q-type channel protein fragments from two different human CT splice variants, as predicted from SCA6 patients, in PCs of mice using viral and transgenic approaches. These splice variants represent a short (CT-short without polyQs) and a long (CT-long with 27 polyQs) CT fragment. Our results show that the different splice variants of the CTs differentially distribute within PCs, i.e., the short CTs reveal predominantly nuclear inclusions, whereas the long CTs prominently reveal both nuclear and cytoplasmic aggregates. Postnatal expression of CTs in PCs in mice reveals that only CT-long causes SCA6-like symptoms, i.e., deficits in eyeblink conditioning (EBC), ataxia, and PC degeneration. The physiological phenotypes associated specifically with the long CT fragment can be explained by an impairment of LTD and LTP at the parallel fiber-to-PC synapse and alteration in spontaneous PC activity. Thus, our results suggest that the polyQ carrying the CT fragment of the P/Q-type channel is sufficient to cause SCA6 pathogenesis in mice and identifies EBC as a new diagnostic strategy to evaluate Ca2+ channel-mediated human diseases. © 2015 the authors.


Lange I.,Maastricht University | Kasanova Z.,Maastricht University | Goossens L.,Maastricht University | Leibold N.,Maastricht University | And 5 more authors.
Neuroscience and Biobehavioral Reviews | Year: 2015

Recent neuro-imaging studies have implicated the cerebellum in several higher-order functions. Its role in human fear conditioning has, however, received limited attention. The current meta-analysis examines the loci of cerebellar contributions to fear conditioning in healthy subjects, thus mapping, for the first time, the neural response to conditioned aversive stimuli onto the cerebellum. By using the activation likelihood estimation (ALE) technique for analyses, we identified several distinct regions in the cerebellum that activate in response to the presentation of the conditioned stimulus: the cerebellar tonsils, lobules HIV-VI, and the culmen. These regions have separately been implicated in fear acquisition, consolidation of fear memories and expression of conditioned fear responses. Their specific role in these processes may be attributed to the general contribution of cerebellar cortical networks to timing and prediction. Our meta-analysis highlights the potential role of the cerebellum in human cognition and emotion in general, and addresses the possibility how deficits in associative cerebellar learning may play a role in the pathogenesis of anxiety disorders. Future studies are needed to further clarify the mechanistic role of the cerebellum in higher order functions and neuropsychiatric disorders. © 2015.


Raike R.S.,Emory University | Weisz C.,Johns Hopkins University | Hoebeek F.E.,Erasmus Medical Center | Terzi M.C.,Emory University | And 5 more authors.
Neurobiology of Disease | Year: 2013

Several episodic neurological disorders are caused by ion channel gene mutations. In patients, transient neurological dysfunction is often evoked by stress, caffeine and ethanol, but the mechanisms underlying these triggers are unclear because each has diverse and diffuse effects on the CNS. Attacks of motor dysfunction in the CaV2.1 calcium channel mouse mutant tottering are also triggered by stress, caffeine and ethanol. Therefore, we used the tottering mouse attacks to explore the pathomechanisms of the triggers. Despite the diffuse physiological effects of these triggers, ryanodine receptor blockers prevented attacks induced by all of them. In contrast, compounds that potentiate ryanodine receptors triggered attacks suggesting a convergent biochemical pathway. Tottering mouse attacks were both induced and blocked within the cerebellum suggesting that the triggers act locally to instigate attacks. In fact, stress, caffeine and alcohol precipitated attacks in CaV2.1 mutant mice in which genetic pathology was limited to cerebellar Purkinje cells, suggesting that the triggers initiate dysfunction within a specific brain region. The surprising biochemical and anatomical specificity of the triggers and the discovery that the triggers operate through shared mechanisms suggest that it is possible to develop targeted therapies aimed at blocking the induction of episodic neurological dysfunction, rather than treating the symptoms once provoked. © 2012 Elsevier Inc.


Burguiere E.,University Pierre and Marie Curie | Burguiere E.,Massachusetts Institute of Technology | Arabo A.,University Pierre and Marie Curie | Jarlier F.,University Pierre and Marie Curie | And 3 more authors.
Journal of Neuroscience | Year: 2010

Learning a new goal-directed behavioral task often requires the improvement of at least two processes, including an enhanced stimulus-response association and an optimization of the execution of the motor response. The cerebellum has recently been shown to play a role in acquiring goal-directed behavior, but it is unclear to what extent it contributes to a change in the stimulus-response association and/or the optimization of the execution of the motor response.Wetherefore designed the stimulus-dependent water Y-maze conditioning task, which allows discrimination between both processes, and we subsequently subjected Purkinje cell-specific mutant mice to this new task. The mouse mutants L7-PKCi, which suffer from impaired PKC-dependent processes such as parallel fiber to Purkinje cell long-term depression (PF-PC LTD), were able to acquire the stimulus-response association, but exhibited a reduced optimization of their motor performance. These data show that PF-PC LTD is not required for learning a stimulus-response association, but they do suggest that a PKC-dependent process in cerebellar Purkinje cells is required for optimization of motor responses. Copyright © 2010 the authors.


Clopath C.,University of Paris Descartes | Clopath C.,Columbia University | Clopath C.,Imperial College London | Badura A.,Royal Dutch Academy of Arts and science | And 6 more authors.
Journal of Neuroscience | Year: 2014

Mechanisms of cerebellar motor learning are still poorly understood. The standard Marr-Albus-Ito theory posits that learning involves plasticity at the parallel fiber to Purkinje cell synapses under control of the climbing fiber input, which provides an error signal as in classical supervised learning paradigms. However, a growing body of evidence challenges this theory, in that additional sites of plasticity appear to contribute to motor adaptation. Here, we consider phase-reversal training of the vestibulo-ocular reflex (VOR), a simple form of motor learning for which a large body of experimental data is available in wild-type and mutant mice, in which the excitability of granule cells or inhibition of Purkinje cells was affected in a cell-specific fashion. We present novel electrophysiological recordings of Purkinje cell activity measured in naive wild-type mice subjected to this VOR adaptation task. We then introduce a minimal model that consists of learning at the parallel fibers to Purkinje cells with the help of the climbing fibers. Although the minimal model reproduces the behavior of the wild-type animals and is analytically tractable, it fails at reproducing the behavior of mutant mice and the electrophysiology data. Therefore, we build a detailed model involving plasticity at the parallel fibers to Purkinje cells' synapse guided by climbing fibers, feedforward inhibition of Purkinje cells, and plasticity at the mossy fiber to vestibular nuclei neuron synapse. The detailed model reproduces both the behavioral and electrophysiological data of both the wild-type and mutant mice and allows for experimentally testable predictions. © 2014 the authors.


Rahmati N.,Erasmus University Rotterdam | Kunzelmann K.,University of Regensburg | Xu J.,University of Cincinnati | Barone S.,University of Cincinnati | And 6 more authors.
Pflugers Archiv European Journal of Physiology | Year: 2013

SLC26A11 (human)/Slc26a11 (mouse), also known as kidney brain anion transporter (KBAT), is a member of the SLC26 anion transporter family and shows abundant mRNA expression in the brain. However, its exact cellular distribution and subcellular localization in the brain and its functional identity and possible physiological roles remain unknown. Expression and immunostaining studies demonstrated that Slc26a11 is abundantly expressed in the cerebellum, with a predominant expression in Purkinje cells. Lower expression levels were detected in hippocampus, olfactory bulb, cerebral cortex, and subcortical structures. Patch clamp studies in HEK293 cells transfected with mouse cDNA demonstrated that Slc26a11 can function as a chloride channel that is active under basal conditions and is not regulated by calcium, forskolin, or co-expression with cystic fibrosis transmembrane regulator. Single and double immunofluorescent labeling studies demonstrated the localization of vacuolar (V) H+-ATPase and Slc26a11 (KBAT) in the plasma membrane in Purkinje cells. Functional studies in HEK293 cells indicated that transfection with Slc26a11 stimulated acid transport via endogenous V H+-ATPase. We conclude that Slc26a11 (KBAT) is prominently distributed in output neurons of various subcortical and cortical structures in the central nervous system, with specific expression in Purkinje cells and that it may operate as a chloride channel regulating acid translocation by H+-ATPase across the plasma membrane and in intracellular compartments. © 2013 Springer-Verlag Berlin Heidelberg.


Lapid-Gortzak R.,University of Amsterdam | Van Der Meulen I.J.E.,University of Amsterdam | Van Der Linden J.W.,Retina Total Eye Care | Mourits M.P.,University of Amsterdam | Van Den Berg T.J.T.P.,Royal Dutch Academy of Arts and science
Journal of Cataract and Refractive Surgery | Year: 2014

Purpose To report the outcomes of changes in straylight before and after phacoemulsification in eyes with preoperative corrected distance visual acuity (CDVA) better than 0.1 logMAR. Setting Private refractive surgery clinic, Driebergen, the Netherlands. Design Cohort study. Methods Standard phacoemulsification with implantation of a monofocal or multifocal intraocular lens (IOL) was performed. Preoperative and 3-month postoperative straylight values, CDVA, and refractive error were compared. Results The study enrolled 160 eyes (89 patients). The mean CDVA was 0.02 ± 0.05 logMAR (range -0.1 to 0.1 logMAR) preoperatively and 0.00 ± 0.04 logMAR (range -0.1 to 0.2 logMAR) postoperatively. The mean preoperative straylight was 1.21 ± 0.20 log(s) (range 0.80 to 1.74 log[s]) and 1.11 ± 1.16 log(s) (range 0.76 to 1.63 log[s]), respectively; the improvement was statistically significant. There was a correlation between high preoperative straylight values and postoperative improvement in straylight values. Conclusions In eyes with relatively good CDVA of 0.1 logMAR or better (decimal 0.8 or better; Snellen 20/25 or better), straylight improved by 0.10 log(s) after cataract surgery. A subgroup of 44 eyes had an improvement of more than 0.20 log(s), which is comparable to a 2-line improvement on the vision chart. Financial Disclosure(s) Proprietary or commercial disclosures are listed after the references. © 2014 ASCRS and ESCRS.


Voogd J.,Erasmus University Rotterdam | Schraa-Tam C.K.L.,Erasmus University Rotterdam | Van Der Geest J.N.,Erasmus University Rotterdam | De Zeeuw C.I.,Erasmus University Rotterdam | De Zeeuw C.I.,Royal Dutch Academy of Arts and science
Cerebellum | Year: 2012

In this paper, we will review the anatomical components of the visuomotor cerebellum in human and, where possible, in non-human primates and discuss their function in relation to those of extracerebellar visuomotor regions with which they are connected. The floccular lobe, the dorsal paraflocculus, the oculomotor vermis, the uvula- nodulus, and the ansiform lobule are more or less independent components of the visuomotor cerebellum that are involved in different corticocerebellar and/or brain stem olivocerebellar loops. The floccular lobe and the oculomotor vermis share different mossy fiber inputs from the brain stem; the dorsal paraflocculus and the ansiform lobule receive corticopontine mossy fibers from postrolandic visual areas and the frontal eye fields, respectively. Of the visuomotor functions of the cerebellum, the vestibulo-ocular reflex is controlled by the floccular lobe; saccadic eye movements are controlled by the oculomotor vermis and ansiform lobule, while control of smooth pursuit involves all these cerebellar visuomotor regions. Functional imaging studies in humans further emphasize cerebellar involvement in visual reflexive eye movements and are discussed. ©Springer Science+Business Media, LLC 2011.


Lapid-Gortzak R.,Retina Total Eye Care | Lapid-Gortzak R.,University of Amsterdam | Van Der Meulen I.J.E.,Retina Total Eye Care | Van Der Meulen I.J.E.,University of Amsterdam | And 2 more authors.
Journal of Cataract and Refractive Surgery | Year: 2011

In a patient with complaints of photophobia and an ocular deviation, straylight was found to be increased to 1.61 (log[s]), which is 5 times the normal value. The only relative clinical finding was the edge of a too small posterior capsulotomy. Visual acuity was normal. Six weeks after the posterior capsulotomy was widened to a diameter of 6.0 mm with a neodymium:YAG laser, the symptoms were resolved and the patient was satisfied. Straylight may manifest clinically as complaints of photophobia. Straylight increase, which can be related to slitlamp findings, may lead to an interventional decision. Our clinical decision-making was also guided by straylight measurements and proved to be crucial in resolving the patient's complaints. More study of clinical situations in which straylight measurement can be used is needed. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. Additional disclosures are in the footnotes. © 2011 ASCRS and ESCRS.


Coesmans M.,Erasmus University Rotterdam | Coesmans M.,Delta Psychiatric Center | Roder C.H.,Erasmus University Rotterdam | Smit A.E.,Erasmus University Rotterdam | And 5 more authors.
Journal of Psychiatry and Neuroscience | Year: 2014

Background: The notion that cerebellar deficits may underlie clinical symptoms in people with schizophrenia is tested by evaluating 2 forms of cerebellar learning in patients with recent-onset schizophrenia. A potential medication effect is evaluated by including patients with or without antipsychotics. Methods: We assessed saccadic eye movement adaptation and eyeblink conditioning in men with recentonset schizophrenia who were taking antipsychotic medication or who were antipsychotic-free and in age-matched controls. Results: We included 39 men with schizophrenia (10 who were taking clozapine, 16 who were taking haloperidol and 13 who were antipsychoticfree) and 29 controls in our study. All participants showed significant saccadic adaptation. Adaptation strength did not differ between healthy controls and men with schizophrenia. The speed of saccade adaptation, however, was significantly lower in men with schizophrenia. They showed a significantly lower increase in the number of conditioned eyeblink responses. Over all experiments, no consist - ent effects of medication were observed. These outcomes did not correlate with age, years of education, psychopathology or dose of anti psychotics. Limitations: As patients were not randomized for treatment, an influence of confounding variables associated with medi - cation status cannot be excluded. Individual patients also varied along the schizophrenia spectrum despite the relative homogeneity with respect to onset of illness and short usage of medication. Finally, the relatively small number of participants may have concealed effects as a result of insufficient statistical power. Conclusion: We found several cerebellar learning deficits in men with schizophrenia that we cannot attribute to the use of antipsychotics. Although this finding, combined with the fact that deficits are already present in patients with recent-onset schizophrenia, could suggest that cerebellar impairments are a trait deficit in people with schizophrenia. This should be confirmed in longitudinal studies. © 2014 Canadian Medical Association.

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