Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain

Göttingen, Germany

Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain

Göttingen, Germany
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Papiol S.,Max Planck Institute for Experimental Medicine | Papiol S.,Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain | Mitjans M.,Max Planck Institute for Experimental Medicine | Mitjans M.,University of Barcelona | And 8 more authors.
Translational Psychiatry | Year: 2014

A recent publication reported an exciting polygenic effect of schizophrenia (SCZ) risk variants, identified by a large genome-wide association study (GWAS), on total brain and white matter volumes in schizophrenic patients and, even more prominently, in healthy subjects. The aim of the present work was to replicate and then potentially extend these findings. According to the original publication, polygenic risk scores - using single nucleotide polymorphism (SNP) information of SCZ GWAS - (polygenic SCZ risk scores; PSS) were calculated in 122 healthy subjects, enrolled in a structural magnetic resonance imaging (MRI) study. These scores were computed based on P-values and odds ratios available through the Psychiatric GWAS Consortium. In addition, polygenic white matter scores (PWM) were calculated, using the respective SNP subset in the original publication. None of the polygenic scores, either PSS or PWM, were found to be associated with total brain, white matter or gray matter volume in our replicate sample. Minor differences between the original and the present study that might have contributed to lack of reproducibility (but unlikely explain it fully), are number of subjects, ethnicity, age distribution, array technology, SNP imputation quality and MRI scanner type. In contrast to the original publication, our results do not reveal the slightest signal of association of the described sets of GWAS-identified SCZ risk variants with brain volumes in adults. Caution is indicated in interpreting studies building on polygenic risk scores without replication sample. © 2014 Macmillan Publishers Limited All rights reserved.

Oku Y.,Hyogo College of Medicine | Fresemann J.,University of Gottingen | Miwakeichi F.,The Institute of Statistical Mathematics of Tokyo | Miwakeichi F.,Graduate University for Advanced Studies | And 2 more authors.
Respiratory Physiology and Neurobiology | Year: 2015

Astrocytes have been found to modulate neuronal activity through calcium-dependent signaling in various brain regions. However, whether astrocytes of the pre-Bötzinger complex (preBötC) exhibit respiratory rhythmic fluctuations is still controversial. Here we evaluated calcium-imaging experiments within preBötC in rhythmically active medullary slices from TgN(hGFAP-EGFP) mice using advanced analyses. 13.8% of EGFP-negative cells, putative neurons, showed rhythmic fluorescent changes that were highly correlated to the respiratory rhythmic fluctuation (cross-correlation coefficient. > 0.5 and d. F/. F . > 0.2%). In contrast, a considerable number of astrocyte somata exhibited synchronized low-frequency (<0.03. Hz) calcium oscillations. After band-pass filtering, signals that irregularly preceded the calcium signal of EGFP-negative cells were observed in 10.2% of astrocytes, indicating a functional coupling between astrocytes and neurons in preBötC. A model simulation confirmed that such preinspiratory astrocytic signals can arise from coupled neuronal and astrocytic oscillators, supporting a concept that slow oscillatory changes of astrocytic functions modulate neighboring neuronal activity to add variability in respiratory rhythm. © 2015 Elsevier B.V.

Stepniak B.,Max Planck Institute for Experimental Medicine | Papiol S.,Max Planck Institute for Experimental Medicine | Papiol S.,Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain | Hammer C.,Max Planck Institute for Experimental Medicine | And 6 more authors.
The Lancet Psychiatry | Year: 2014

Background: Schizophrenia is caused by a combination of genetic and environmental factors, as first evidenced by twin studies. Extensive efforts have been made to identify the genetic roots of schizophrenia, including large genome-wide association studies, but these yielded very small effect sizes for individual markers. In this study, we aimed to assess the relative contribution of genome-wide association study-derived genetic versus environmental risk factors to crucial determinants of schizophrenia severity: disease onset, disease severity, and socioeconomic measures. Methods: In this parallel analysis, we studied 750 male patients from the Göttingen Research Association for Schizophrenia (GRAS) dataset (Germany) with schizophrenia for whom both genome-wide coverage of single-nucleotide polymorphisms and deep clinical phenotyping data were available. Specifically, we investigated the potential effect of schizophrenia risk alleles as identified in the most recent large genome-wide association study versus the effects of environmental hazards (ie, perinatal brain insults, cannabis use, neurotrauma, psychotrauma, urbanicity, and migration), alone and upon accumulation, on age at disease onset, age at prodrome, symptom expression, and socioeconomic parameters. Findings: In this study, we could show that frequent environmental factors become a major risk for early schizophrenia onset when accumulated (prodrome begins up to 9 years earlier; p=2·×10-10). In particular, cannabis use-an avoidable environmental risk factor-is highly significantly associated with earlier age at prodrome (p=3·8×10-20). By contrast, polygenic genome-wide association study risk scores did not have any detectable effects on schizophrenia phenotypes. Interpretation: These findings should be translated to preventive measures to reduce environmental risk factors, since age at onset of schizophrenia is a crucial determinant of an affected individual's fate and the total socioeconomic cost of the illness. Funding: German Research Foundation (Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain), Max Planck Society, Max Planck Förderstiftung, EXTRABRAIN EU-FP7, ERA-NET NEURON. © 2014 Elsevier Ltd.

Kastner A.,Max Planck Institute for Experimental Medicine | Begemann M.,Max Planck Institute for Experimental Medicine | Begemann M.,Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain | Michel T.M.,University of Southern Denmark | And 9 more authors.
BMC Psychiatry | Year: 2015

Background: Behavioral phenotypical continua from health to disease suggest common underlying mechanisms with quantitative rather than qualitative differences. Until recently, autism spectrum disorders and schizophrenia were considered distinct nosologic entities. However, emerging evidence contributes to the blurring of symptomatic and genetic boundaries between these conditions. The present study aimed at quantifying behavioral phenotypes shared by autism spectrum disorders and schizophrenia to prepare the ground for biological pathway analyses. Methods: Specific items of the Positive and Negative Syndrome Scale were employed and summed up to form a dimensional autism severity score (PAUSS). The score was created in a schizophrenia sample (N = 1156) and validated in adult high-functioning autism spectrum disorder (ASD) patients (N = 165). To this end, the Autism Diagnostic Observation Schedule (ADOS), the Autism (AQ) and Empathy Quotient (EQ) self-rating questionnaires were applied back to back with the newly developed PAUSS. Results: PAUSS differentiated between ASD, schizophrenia and a disease-control sample and substantially correlated with the Autism Diagnostic Observation Schedule. Patients with ADOS scores ≥12 obtained highest, those with scores <7 lowest PAUSS values. AQ and EQ were not found to vary dependent on ADOS diagnosis. ROC curves for ADOS and PAUSS resulted in AuC values of 0.9 and 0.8, whereas AQ and EQ performed at chance level in the prediction of ASD. Conclusions: This work underscores the convergence of schizophrenia negative symptoms and autistic phenotypes. PAUSS evolved as a measure capturing the continuous nature of autistic behaviors. The definition of extreme-groups based on the dimensional PAUSS may permit future investigations of genetic constellations modulating autistic phenotypes. © Kästner et al.; licensee BioMed Central.

Hammer C.,Max Planck Institute for Experimental Medicine | Wanitchakoo P.,University of Regensburg | Sirianant L.,University of Regensburg | Papiol S.,Max Planck Institute for Experimental Medicine | And 16 more authors.
Molecular Medicine | Year: 2015

In a first genome-wide association study (GWAS) approach to anti-Borrelia seropositivity, we identified two significant single nucleotide polymorphisms (SNPs) (rs17850869, P = 4.17E-09; rs41289586, P = 7.18E-08). Both markers, located on chromosomes 16 and 3, respectively, are within or close to genes previously connected to spinocerebellar ataxia. The risk SNP rs41289586 represents a missense variant (R263H) of anoctamin 10 (ANO10), a member of a protein family encoding Cl– channels and phospholipid scramblases. ANO10 augments volume-regulated Cl– currents (IHypo) in Xenopus oocytes, HEK293 cells, lymphocytes and macrophages and controls volume regulation by enhancing regulatory volume decrease (RVD). ANO10 supports migration of macrophages and phagocytosis of spirochetes. The R263H variant is inhibitory on IHypo, RVD and intracellular Ca2+ signals, which may delay spirochete clearance, thereby sensitizing adaptive immunity. Our data demonstrate for the first time that ANO10 has a central role in innate immune defense against Borrelia infection. © 2015 Molecular Medicine. All rights received.

Netrakanti P.R.,Max Planck Institute for Experimental Medicine | Cooper B.H.,Max Planck Institute for Experimental Medicine | Dere E.,Max Planck Institute for Experimental Medicine | Poggi G.,Max Planck Institute for Experimental Medicine | And 6 more authors.
Cerebellum | Year: 2015

Munc13-3 is a member of the Munc13 family of synaptic vesicle priming proteins and mainly expressed in cerebellar neurons. Munc13-3 null mutant (Munc13-3−/−) mice show decreased synaptic release probability at parallel fiber to Purkinje cell, granule cell to Golgi cell, and granule cell to basket cell synapses and exhibit a motor learning deficit at highest rotarod speeds. Since we detected Munc13-3 immunoreactivity in the dentate gyrus, as reported here for the first time, and current studies indicated a crucial role for the cerebellum in hippocampus-dependent spatial memory, we systematically investigated Munc13-3−/− mice versus wild-type littermates of both genders with respect to hippocampus-related cognition and a range of basic behaviors, including tests for anxiety, sensory functions, motor performance and balance, sensorimotor gating, social interaction and competence, and repetitive and compulsive behaviors. Neither basic behavior nor hippocampus-dependent cognitive performance, evaluated by Morris water maze, hole board working and reference memory, IntelliCage-based place learning including multiple reversals, and fear conditioning, showed any difference between genotypes. However, consistent with a disturbed cerebellar reflex circuitry, a reliable reduction in the acoustic startle response in both male and female Munc13-3−/− mice was found. To conclude, complete deletion of Munc13-3 leads to a robust decrease in the acoustic startle response. This readout of a fast cerebellar reflex circuitry obviously requires synaptic vesicle priming by Munc13-3 for full functionality, in contrast to other behavioral or cognitive features, where a nearly perfect compensation of Munc13-3 deficiency by related synaptic proteins has to be assumed. © 2015, The Author(s).

Borger M.,University of Gottingen | Funke S.,University of Mainz | Bahr M.,University of Gottingen | Bahr M.,Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain | And 3 more authors.
Basal Ganglia | Year: 2015

Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. In nearby future its importance will increase, especially due to changes in age structure. There are still substantial problems in terms of early diagnosis of the disease. In clinical practice, the diagnosis of PD is still based on the evaluation of clinical presentation and is supported by various ancillary tests with heterogeneous predictive value. In regard to diagnosis and disease monitoring, body fluid-based biomarkers have become an indispensable tool in today's medicine. In this Current Opinion we briefly address the present approaches to biomarker development for PD, including clinical trials on blood-based, cerebrospinal fluid-based and other body fluid-based biomarkers. We then review the knowledge on tear fluid-based biomarkers in general and discuss its usability as a source for biomarkers in PD patients. The close spatial relation of the lacrimal glands to the cranial nerves may predispose tear fluid to mirror pathophysiological changes in the central nervous system and argues for its validation as a biomarker in clinical studies. Based on the requirements for clinically useful biomarkers, we propose that tear fluid may serve as an easily accessible source for biomarkers in patients with PD and other neurodegenerative movement disorders. © 2015 Elsevier GmbH.

Carboni E.,University of Gottingen | Carboni E.,Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain | Lingor P.,University of Gottingen | Lingor P.,Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain
Metallomics | Year: 2015

Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder with severe consequences for patients and caregivers. In the last twenty years of research, alpha-synuclein (αSyn) emerged as a main regulator of PD pathology, both in genetic and sporadic cases. Most importantly, oligomeric and aggregated species of αSyn appear to be pathogenic. In addition, transition metals have been implicated in the disease pathogenesis of PD already for decades. The interaction of metals with αSyn has been shown to trigger the aggregation of this protein. Furthermore, metals can exert cellular toxicity due to their red-ox potential, which leads to the formation of reactive oxygen species, exacerbating the noxious effects of αSyn. Here we give a brief overview on αSyn pathology and the role of metals in the brain and then address in more detail the interaction of αSyn with three disease-relevant transition metals, iron (Fe), copper (Cu) and manganese (Mn). We also discuss possible therapeutic approaches for PD, which are based on these interactions, e.g. chelation therapy and anti-oxidative treatments. Not all mechanisms of alpha-synuclein-mediated toxicity and roles of metals are sufficiently understood. We discuss several aspects, which deserve further investigation in order to shed light on the etiopathology of the disease and enable the development of more specific, innovative drugs for the treatment of PD and other synucleinopathies. © 2015 The Royal Society of Chemistry.

Woehler A.,Max Planck Institute for Biophysical Chemistry | Woehler A.,Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain | Lin K.-H.,Max Planck Institute for Biophysical Chemistry | Neher E.,Max Planck Institute for Biophysical Chemistry | Neher E.,Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain
Journal of Physiology | Year: 2014

Significantly more Ca2+ influx is required for eliciting release of neurotransmitter during whole cell patch clamp recording in the Calyx of Held, when gluconate with 3 mM free ATP is used as pipette filling solution, as compared to a methanesulfonate-based solution with excess Mg2+. This reduction in efficiency of Ca2+ in eliciting release is due to low-affinity Ca2+ binding of both gluconate and ATP2- anions. To study these effects we developed a simple fluorimeteric titration procedure, which reports the dissociation constant, KD, of a given Ca2+ indicator dye, multiplied by 1 plus the sum of Ca2+ binding ratios of any anions, which act as low-affinity Ca2+ ligands. For solutions without Ca2+ binding anions we find KD values for Fura2FF ranging from 11.5 ± 1.7 to 15.6 ± 7.47 μM depending on the dominant anion used. For Fura6F and KCl-based solutions we find KD = 17.8 ± 1.3 μM. For solutions with gluconate as the main anion and for solutions that contain nucleotides, such as ATP and GTP, we findmuch higher values for the product. Assuming that the KD of the indicator dye is equal to that of KCl-based solutions we calculate the summed Ca2+ binding ratios and find a value of 3.55 for a solution containing 100 mM potassium gluconate and 4 mM ATP. Gluconate contributes a value of 1.75 to this number, while the contribution of ATP depends strongly on the presence of Mg2+ and varies from 0.8 (with excess Mg2+) to 13.8 (in the presence of 3 mM free ATP). Methanesulfonate has negligible Ca2+ binding capacity. These results explain the reduced efficiency of Ca2+ influx in the presence of gluconate or nucleotides, as these anions are expected to intercept Ca2+ ions at short distance. © 2014 The Authors.

Kermer P.,Nordwest Krankenhaus Sanderbusch | Kermer P.,Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain | Kohn A.,University of Gottingen | Kohn A.,Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain | And 10 more authors.
Journal of Molecular Neuroscience | Year: 2014

Bcl-2-associated athanogene-1 (BAG1) is a multifunctional protein comprising co-chaperone function, increasing Hsp70 foldase activity and chaperone-dependent protein degradation of misfolded substrates, with anti-apoptotic activity. It is neuroprotective in different models of neurological diseases, like cerebral ischemia and Huntington’s disease. In the context of Parkinson’s disease, it has recently been shown to restore DJ-1 function in an in vitro model of hereditary Parkinson’s disease. Here, we demonstrate that BAG1 overexpression in SH-SY5Y cells reduces toxicity after transfection of disease-related α-synuclein mutants. Furthermore, it protects from rotenone-induced cell death in vitro and ameliorates neuronal demise in an in vivo 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) model for Parkinson’s disease after adeno-associated virus (AAV)-mediated BAG1 gene transfer into the substantia nigra in mice but showed no protective effects in an in vitro 6-hydroxidopamine model. In conclusion, we present BAG1 as a potential therapeutic target in Parkinson’s disease. © 2014, Springer Science+Business Media New York.

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