Netherlands Institute of Neuroscience

Amsterdam, Netherlands

Netherlands Institute of Neuroscience

Amsterdam, Netherlands
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Stoenica L.,Charité - Medical University of Berlin | Wilkars W.,University of Hamburg | Battefeld A.,Charité - Medical University of Berlin | Battefeld A.,Netherlands Institute of Neuroscience | And 4 more authors.
Developmental Neurobiology | Year: 2013

The distribution of ion channels in neurons regulates neuronal activity and proper formation of neuronal networks during neuronal development. One of the channels is the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel constituting the molecular substrate of hyperpolarization-activated current (Ih). Our previous study implied a role for the fastest activating subunit HCN1 in the generation of Ih in rat neonatal cortical plate neurons. To better understand the impact of HCN1 in early neocortical development, we here performed biochemical analysis and whole-cell recordings in neonatal cortical plate and juvenile layer 5 somatosensory neurons of HCN1-/- and control HCN1+/+ mice. Western Blot analysis revealed that HCN1 protein expression in neonatal cortical plate tissue of HCN+/+ mice amounted to only 3% of the HCN1 in young adult cortex and suggested that in HCN1-/- mice other isoforms (particularly HCN4) might be compensatory up-regulated. At the first day after birth, functional ablation of the HCN1 subunit did not affect the proportion of Ih expressing pyramidal cortical plate neurons. Although the contribution of individual subunit proteins remains open, the lack of HCN1 markedly slowed the current activation and deactivation in individual Ih expressing neurons. However, it did not impair maximal amplitude/density, voltage dependence of activation, and cAMP sensitivity. In conclusion, our data imply that, although expression is relatively low, HCN1 contributes substantially to Ih properties in individual cortical plate neurons. These properties are significantly changed in HCN1-/-, either due to the lack of HCN1 itself or due to compensatory mechanisms. © 2013 Wiley Periodicals, Inc.

Stadler K.,Charité - Medical University of Berlin | Bierwirth C.,University of Rostock | Stoenica L.,Charité - Medical University of Berlin | Battefeld A.,Charité - Medical University of Berlin | And 13 more authors.
Cerebral Cortex | Year: 2014

Central nervous system (CNS) inflammation involves the generation of inducible cytokines such as interferons (IFNs) and alterations in brain activity, yet the interplay of both is not well understood. Here, we show that in vivo elevation of IFNs by viral brain infection reduced hyperpolarization- activated currents (Ih) in cortical pyramidal neurons. In rodent brain slices directly exposed to type I IFNs, the hyperpolarization-activated cyclic nucleotide (HCN)-gated channel subunit HCN1 was specifically affected. The effect required an intact type I receptor (IFNAR) signaling cascade. Consistent with Ih inhibition, IFNs hyperpolarized the resting membrane potential, shifted the resonance frequency, and increased the membrane impedance. In vivo application of IFN-β to the rat and to the mouse cerebral cortex reduced the power of higher frequencies in the cortical electroencephalographic activity only in the presence of HCN1. In summary, these findings identify HCN1 channels as a novel neural target for type I IFNs providing the possibility to tune neural responses during the complex event of a CNS inflammation. © The Author 2012.

Wacongne C.,French Institute of Health and Medical Research | Wacongne C.,CEA Saclay Nuclear Research Center | Wacongne C.,University Paris - Sud | Wacongne C.,Collège de France | Wacongne C.,Netherlands Institute of Neuroscience
Biological Psychology | Year: 2016

The mismatch negativity (MMN) is thought to be an index of the automatic activation of a specialized network for active prediction and deviance detection in the auditory cortex. It is consistently reduced in schizophrenic patients and has received a lot of interest as a clinical and translational tool. The main neuronal hypothesis regarding the mechanisms leading to a reduced MMN in schizophrenic patients is a dysfunction of NMDA receptors (NMDA-R). However, this hypothesis has never been implemented in a neuronal model. In this paper, we examine the consequences of NMDA-R dysfunction in a neuronal model of MMN based on predictive coding principle. I also investigate how predictive processes may interact with synaptic adaptation in MMN generations and examine the consequences of this interaction for the use of MMN paradigms in schizophrenia research. © 2015 Elsevier B.V.

Littink K.W.,Rotterdam Eye Hospital | Littink K.W.,Radboud University Nijmegen | Van Genderen M.M.,Bartimeus Institute for the Visually Impaired | Van Schooneveld M.J.,Netherlands Institute of Neuroscience | And 9 more authors.
Ophthalmology | Year: 2012

Purpose: To determine the genetic defect and to describe the clinical characteristics in patients with retinitis punctata albescens (RPA) and fundus albipunctatus (FAP). Design: Case series/observational study. Participants: We included 13 patients affected by RPA or FAP. Methods: Thirteen patients were collected from 8 families with a retinal dystrophy characterized by tiny, yellow-white dots on funduscopy, typical for FAP or RPA. All patients underwent full ophthalmologic examinations, including visual field assessment. Fundus photography, and electroretinography were performed in 12 patients, and optical coherence tomography and fundus autofluorescence were performed in 4 patients. DNA samples of all patients were screened for mutations in RLBP1 and for mutations in RDH5 in patients who did not carry mutations in RLBP1. DNA samples of 2 sibling pairs of nonconsanguineous families who carried mutations neither in RLBP1 nor in RDH5 were analyzed by genome-wide homozygosity mapping. Sequence analysis was performed of LRAT, a candidate gene in a shared homozygous region. Main Outcome Measures: We assessed DNA sequence variants, best-corrected visual acuity, fundus appearance, visual field measurements, electroretinogram responses, optical coherence tomography, and fundus autofluorescence. Results: A homozygous frameshift mutation was identified in LRAT in 4 patients with RPA. Mutations in RLBP1 were identified in 7 patients with RPA and in 1 patient with FAP and cone dystrophy. One patient had compound heterozygous mutations in RDH5 and suffered from FAP with mild maculopathy. Conclusions: A genetic defect was identified in LRAT as a novel cause of RPA. LRAT is therefore the fourth gene involved in the visual cycle that may cause a white-dot retinopathy. We also revealed that mutations in RLBP1 may lead to FAP with cone dystrophy. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. © 2012 American Academy of Ophthalmology.

Collin R.W.J.,Radboud University Nijmegen | van den Born L.I.,Rotterdam Eye Hospital | Klevering B.J.,Radboud University Nijmegen | de Castro-Miro M.,Radboud University Nijmegen | And 19 more authors.
Investigative Ophthalmology and Visual Science | Year: 2011

PURPOSE. To determine the genetic defects underlying autosomal recessive retinitis pigmentosa (arRP) in the Dutch population and in a subset of patients originating from other countries. The hypothesis was that, because there has been little migration over the past centuries in certain areas of The Netherlands, a significant fraction of Dutch arRP patients carry their genetic defect in the homozygous state. METHODS. High-resolution genome-wide SNP genotyping on SNP arrays and subsequent homozygosity mapping were performed in a large cohort of 186 mainly nonconsanguineous arRP families living in The Netherlands. Candidate genes residing in homozygous regions were sequenced. RESULTS. In ~94% of the affected individuals, large homozygous sequences were identified in their genome. In 42 probands, at least one of these homozygous regions contained one of the 26 known arRP genes. Sequence analysis of the corresponding genes in each of these patients revealed 21 mutations and two possible pathogenic changes, 14 of which were novel. All mutations were identified in only a single family, illustrating the genetic diversity within the Dutch population. CONCLUSIONS. This report demonstrates that homozygosity mapping is a powerful tool for identifying the genetic defect underlying genetically heterogeneous recessive disorders like RP, even in populations with little consanguinity. © 2011 The Association for Research in Vision and Ophthalmology, Inc.

Chakravarthy U.,Queen's University of Belfast | McKay G.J.,Queen's University of Belfast | De Jong P.T.V.M.,Netherlands Institute of Neuroscience | Rahu M.,National Institute for Health Development | And 10 more authors.
Ophthalmology | Year: 2013

Objective: To study associations between severity stages of early and late age-related macular degeneration (AMD) and genetic variations in age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) and to investigate potential interactions between smoking and ARMS2. Design: Population-based, cross-sectional European Eye Study in 7 countries in Europe. Participants: Four thousand seven hundred fifty participants, 65 years of age and older, recruited through random sampling. Methods: Participants were classified on the basis of the more severely affected eye into 5 mutually exclusive AMD severity stages ranging from no AMD, 3 categories of early AMD, and late AMD. History of cigarette smoking was available and allowed classification into never, former, and current smokers, with the latter 2 groups combined into a single category of ever smokers for analysis. Genotyping was performed for single nucleotide polymorphisms rs10490924 and rs4146894 in ARMS2 and rs1061170 in CFH. Associations were analyzed by logistic regression. Main Outcome Measures: Odds ratios (ORs) for stage of AMD associated with genetic variations in ARMS2 and CFH and interactions between ARMS2 and smoking status. Results: Early AMD was present in 36.4% and late AMD was present in 3.3% of participants. Data on both genotype and AMD were available for 4276 people. The ORs for associations between AMD stage and ARMS2 increased monotonically with more severe stages of early AMD and were altered little by adjustment for potential confounders. Compared with persons with no AMD, carriers of the TT genotype for rs10490924 in ARMS2 had a 10-fold increase in risk of late AMD (P<3×10-20). The ORs for associations with CFH were similar for stage 3 early AMD and late AMD. Interactions between rs10490924 in ARMS2 and smoking status were significant in both unadjusted and adjusted models (P = 0.001). The highest risk was observed in those doubly homozygous for rs10490924 and rs1061170 in CFH (OR, 62.3; 95% confidence interval, 16-242), with P values for trend ranging from 0.03 (early AMD, stage 1) to 1×10-26 (late AMD). Conclusions: A strong association was demonstrated between all stages of AMD and genetic variation in ARMS2, and a significant gene-environment interaction with cigarette smoking was confirmed. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. © 2013 American Academy of Ophthalmology.

Brock O.,Netherlands Institute of Neuroscience | Bakker J.,University of Liège | Baum M.J.,Boston University
Methods in Molecular Biology | Year: 2013

Behavioral testing methods are described for determining whether female mice can discriminate between volatile urinary pheromones of conspecifics of the same vs. opposite sex and/or in different endocrine conditions, for determining sexual partner preference, for quantifying receptive (lordosis) behavior, and for monitoring the expression of male-typical mounting behavior in female mice. © 2013 Springer Science+Business Media, LLC.

de Oliveira R.B.,University of Newcastle | Graham B.,University of Newcastle | Howlett M.C.H.,University of Newcastle | Howlett M.C.H.,Netherlands Institute of Neuroscience | And 8 more authors.
Journal of Neuroscience Methods | Year: 2010

The dissociative anesthetic ketamine that acts as an N-methyl-D-aspartate (NMDA) antagonist has been reported to improve neurological damage after experimental ischemic challenges. Here we show that deep anesthesia with ketamine before euthanasia by decapitation improves the quality of neonatal mouse neuronal brain slice preparations. Specifically we found that neurons of the locus coeruleus (LC) and hypoglossal motor neurons had significantly higher input resistances, and LC neurons that generally are difficult to voltage control, could be more reliably voltage clamped compared to control neurons. © 2010 Elsevier B.V.

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