Leibniz Institute for Neurobiology Magdeburg

Magdeburg, Germany

Leibniz Institute for Neurobiology Magdeburg

Magdeburg, Germany

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Valenzuela J.C.,Leibniz Institute for Neurobiology Magdeburg | Heise C.,Leibniz Institute for Neurobiology Magdeburg | Heise C.,CNR Institute of Neuroscience | Franken G.,Leibniz Institute for Neurobiology Magdeburg | And 6 more authors.
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

Neuronal networks are balanced by mechanisms of homeostatic plasticity, which adjusts synaptic strength via molecular and morphological changes in the pre- and post-synapse. Here, we wondered whether the hyaluronic acid-based extracellular matrix (ECM) of the brain is involved in mechanisms of homeostatic plasticity. We hypothesized that the ECM, being rich in chondroitin sulfate proteoglycans such as brevican, which are suggested to stabilize synapses by their inhibitory effect on structural plasticity, must be remodelled to allow for structural and molecular changes during conditions of homeostatic plasticity. We found a high abundance of cleaved brevican fragments throughout the hippocampus and cortex and in neuronal cultures, with the strongest labelling in perineuronal nets on parvalbuminpositive interneurons. Using an antibody specific for a brevican fragment cleaved by the matrix metalloprotease ADAMTS4, we identified the enzyme as the main brevican-processing protease. Interestingly, we found ADAMTS4 largely associated with synapses. After inducing homeostatic plasticity in neuronal cell cultures by prolonged network inactivation, we found increased brevican processing at inhibitory as well as excitatory synapses, which is in line with the ADAMTS4 subcellular localization. Thus, the ECM is remodelled in conditions of homeostatic plasticity, whichmay liberate synapses to allow for a higher degree of structural plasticity. & 2014 The Authors.


Gellerich F.N.,Leibniz Institute for Neurobiology Magdeburg | Gellerich F.N.,Otto Von Guericke University of Magdeburg | Gizatullina Z.,Leibniz Institute for Neurobiology Magdeburg | Gainutdinov T.,Academy of Science of the Republic Tatarstan | And 5 more authors.
IUBMB Life | Year: 2013

This review focuses on problems of the intracellular regulation of mitochondrial function in the brain via the (i) supply of mitochondria with ADP by means of ADP shuttles and channels and (ii) the Ca2+ control of mitochondrial substrate supply. The permeability of the mitochondrial outer membrane for adenine nucleotides is low. Therefore rate dependent concentration gradients exist between the mitochondrial intermembrane space and the cytosol. The existence of dynamic ADP gradients is an important precondition for the functioning of ADP shuttles, for example CrP-shuttle. Cr at mM concentrations instead of ADP diffuses from the cytosol through the porin pores into the intermembrane space. The CrP-shuttle isoenzymes work in different directions which requires different metabolite concentrations mainly caused by dynamic ADP compartmentation. The ADP shuttle mechanisms alone cannot explain the load dependent changes in mitochondrial energization, and a complete model of mitochondrial regulation have to account the Ca2+-dependent substrate supply too. According to the old paradigmatic view, Ca2+ cyt taken up by the mitochondrial Ca2+ uniporter activates dehydrogenases within the matrix. However, recently it was found that Ca 2+ cyt at low nM concentrations exclusively activates the state 3 respiration via aralar, the mitochondrial glutamate/aspartate carrier. At higher Ca2+ cyt (> 500 nM), brain mitochondria take up Ca2+ for activation of substrate oxidation rates. Since brain mitochondrial pyruvate oxidation is only slightly influenced by Ca 2+ cyt, it was proposed that the cytosolic formation of pyruvate from its precursors is tightly controlled by the Ca 2+dependent malate/aspartate shuttle. At low (50-100 nM) Ca 2+ cyt the pyruvate formation is suppressed, providing a substrate limitation control in neurons. This so called "gas pedal" mechanism explains why the energy metabolism of neurons in the nucleus suprachiasmaticus could be down-regulated at night but activated at day as a basis for the circadian changes in Ca2+ cyt. It also could explain the energetic disadvantages caused by altered Ca2+ cyt at mitochondrial diseases and neurodegeneration. © 2013 IUBMB Life, 65(3):180-190, 2013 Copyright © 2013 International Union of Biochemistry and Molecular Biology, Inc.


PubMed | Leibniz Institute for Neurobiology Magdeburg, University of Cardiff and University of Hamburg
Type: | Journal: Frontiers in molecular neuroscience | Year: 2016

A central pathway in synaptic plasticity couples N-Methyl-D-Aspartate-receptor (NMDAR)-signaling to the activation of extracellular signal-regulated kinases (ERKs) cascade. ERK-dependency has been demonstrated for several forms of synaptic plasticity as well as learning and memory and includes local synaptic processes but also long-distance signaling to the nucleus. It is, however, controversial how NMDAR signals are connected to ERK activation in dendritic spines and nuclear import of ERK. The synapto-nuclear messenger Jacob couples NMDAR-dependent Ca(2+)-signaling to CREB-mediated gene expression. Protein transport of Jacob from synapse to nucleus essentially requires activation of GluN2B-containing NMDARs. Subsequent phosphorylation and binding of ERK1/2 to and ERK-dependent phosphorylation of serine 180 in Jacob encodes synaptic but not extrasynaptic NMDAR activation. In this study we show that stimulation of synaptic NMDAR in hippocampal primary neurons and induction of long-term potentiation (LTP) in acute slices results in GluN2B-dependent activation of CaMKII- and subsequent nuclear import of active ERK and serine 180 phosphorylated Jacob. On the contrary, no evidence was found that either GluN2A-containing NMDAR or RasGRF2 are upstream of ERK activation and nuclear import of Jacob and ERK.


Krautwald K.,Functional Neuroimaging Group | Angenstein F.,Leibniz Institute for Neurobiology Magdeburg | Angenstein F.,Otto Von Guericke University of Magdeburg | Angenstein F.,Center for Behavioural Brain science
Journal of Cerebral Blood Flow and Metabolism | Year: 2012

To study how various anesthetics affect the relationship between stimulus frequency and generated functional magnetic resonance imaging (fMRI) signals in the rat dentate gyrus, the perforant pathway was electrically stimulated with repetitive low frequency (i.e., 0.625, 1.25, 2.5, 5, and 10 Hz) stimulation trains under isoflurane/N 2 O, isoflurane, medetomidine, and α-chloralose. During stimulation, the blood oxygen level-dependent signal intensity (BOLD response) and local field potentials in the dentate gyrus were simultaneously recorded to prove whether the present anesthetic controls the generation of a BOLD response via targeting general hemodynamic parameters, by affecting mechanisms of neurovascular coupling, or by disrupting local signal processing. Using this combined electrophysiological/fMRI approach, we found that the threshold frequency (i.e., the minimal frequency required to trigger significant BOLD responses), the optimal frequency (i.e., the frequency that elicit the strongest BOLD response), and the spatial distribution of generated BOLD responses are specific for each anesthetic used. Concurrent with anesthetic-dependent characteristics of the BOLD response, we found the pattern of stimulus-induced neuronal activity in the dentate gyrus is also specific for each anesthetic. Consequently, the anesthetic-specific influence on local signaling processes is the underlying cause for the observation that an identical stimulus elicits different BOLD responses under various anesthetics. © 2012 ISCBFM All rights reserved.


Dieterich D.C.,Otto Von Guericke University of Magdeburg | Dieterich D.C.,Leibniz Institute for Neurobiology Magdeburg | Dieterich D.C.,Leibniz Institute for Neurobiology | Kreutz M.R.,Leibniz Institute for Neurobiology | Kreutz M.R.,Center for Behavioral Brain science
Molecular and Cellular Proteomics | Year: 2016

The advances in mass spectrometry based proteomics in the past 15 years have contributed to a deeper appreciation of protein networks and the composition of functional synaptic protein complexes. However, research on protein dynamics underlying core mechanisms of synaptic plasticity in brain lag far behind. In this review, we provide a synopsis on proteomic research addressing various aspects of synaptic function. We discuss the major topics in the study of protein dynamics of the chemical synapse and the limitations of current methodology. We highlight recent developments and the future importance of multidimensional proteomics and metabolic labeling. Finally, emphasis is given on the conceptual framework of modern proteomics and its current shortcomings in the quest to gain a deeper understanding of synaptic plasticity. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.


Bernstein H.-G.,Otto Von Guericke University of Magdeburg | Dobrowolny H.,Otto Von Guericke University of Magdeburg | Schott B.H.,Leibniz Institute for Neurobiology Magdeburg | Gorny X.,Leibniz Institute for Neurobiology Magdeburg | And 4 more authors.
Journal of Psychiatric Research | Year: 2013

Brain anatomical abnormalities as well as cognitive and emotional processing deficits have been reported for the prefrontal cortex in bipolar disorder, which are in part attributable to cellular and laminar abnormalities in postsynaptic protein expression. A kinase anchoring protein (AKAP) 5/79 plays a key role in postsynaptic signalling of excitatory synapses. We aimed to reveal if the cellular expression of AKAP5/79 protein is altered in the anterior cingulate cortex and the dorsolateral prefrontal cortex in bipolar disorder. Ten subjects with bipolar disorder and ten control cases were investigated by use of immunohistochemical and morphometric techniques. Compared with controls in subjects with bipolar disorder, the numerical density of AKAP5-expressing neurons was significantly increased in the left (. p = 0.002) and right (. p = 0.008) anterior cingulate cortex. Layer-specific counting revealed that left side layers II (. p = 0.000), III (. p = 0.001) and V (. p = 0.005) as well as right side layers III (. p = 0.007), IV (. p = 0.007) and V (. p = 0.004) had significantly increased AKAP5-positive cell densities in bipolar disorder. In contrast, no statistically significant differences were found for the dorsolateral prefrontal cortex. However, we observed a more intense intraneuronal immunostaining in both prefrontal areas in bipolar disorder patients. Elevated cell numbers and increased intracellular expression of AKAP, together with the altered expression patterns of most intracellular interaction partners of this protein in bipolar disorder as known from the literature, might point to disease-related abnormalities of the AKAP-associated signalosome in prefrontal cortex neurons. © 2013 Elsevier Ltd.


PubMed | Otto Von Guericke University of Magdeburg and Leibniz Institute for Neurobiology Magdeburg
Type: | Journal: Frontiers in behavioral neuroscience | Year: 2016

Goal directed behavior and associated learning processes are tightly linked to neuronal activity in the ventral striatum. Mechanisms that integrate task relevant sensory information into striatal processing during decision making and learning are implicitly assumed in current reinforcement models, yet they are still weakly understood. To identify the functional activation of cortico-striatal subpopulations of connections during auditory discrimination learning, we trained Mongolian gerbils in a two-way active avoidance task in a shuttlebox to discriminate between falling and rising frequency modulated tones with identical spectral properties. We assessed functional coupling by analyzing the field-field coherence between the auditory cortex and the ventral striatum of animals performing the task. During the course of training, we observed a selective increase of functional coupling during Go-stimulus presentations. These results suggest that the auditory cortex functionally interacts with the ventral striatum during auditory learning and that the strengthening of these functional connections is selectively goal-directed.


PubMed | University of TubingenTubingen, Leibniz Institute for Neurobiology Magdeburg, Ludwig Maximilians University of Munich, German Center for Neurodegenerative Diseases and 3 more.
Type: | Journal: Frontiers in aging neuroscience | Year: 2017

The large number of multicollinear regional features that are provided by resting state (rs) fMRI data requires robust feature selection to uncover consistent networks of functional disconnection in Alzheimers disease (AD). Here, we compared elastic net regularized and classical stepwise logistic regression in respect to consistency of feature selection and diagnostic accuracy using rs-fMRI data from four centers of the German resting-state initiative for diagnostic biomarkers (psymri.org), comprising 53 AD patients and 118 age and sex matched healthy controls. Using all possible pairs of correlations between the time series of rs-fMRI signal from 84 functionally defined brain regions as the initial set of predictor variables, we calculated accuracy of group discrimination and consistency of feature selection with bootstrap cross-validation. Mean areas under the receiver operating characteristic curves as measure of diagnostic accuracy were 0.70 in unregularized and 0.80 in regularized regression. Elastic net regression was insensitive to scanner effects and recovered a consistent network of functional connectivity decline in AD that encompassed parts of the dorsal default mode as well as brain regions involved in attention, executive control, and language processing. Stepwise logistic regression found no consistent network of AD related functional connectivity decline. Regularized regression has high potential to increase diagnostic accuracy and consistency of feature selection from multicollinear functional neuroimaging data in AD. Our findings suggest an extended network of functional alterations in AD, but the diagnostic accuracy of rs-fMRI in this multicenter setting did not reach the benchmark defined for a useful biomarker of AD.


Valenzuela J.C.,Leibniz Institute for Neurobiology Magdeburg | Heise C.,Leibniz Institute for Neurobiology Magdeburg | Franken G.,Leibniz Institute for Neurobiology Magdeburg | Singh J.,Leibniz Institute for Neurobiology Magdeburg | And 3 more authors.
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2014

Neuronal networks are balanced by mechanisms of homeostatic plasticity, which adjusts synaptic strength via molecular and morphological changes in the pre- and post-synapse. Here, we wondered whether the hyaluronic acid-based extracellular matrix (ECM) of the brain is involved in mechanisms of homeostatic plasticity. We hypothesized that the ECM, being rich in chondroitin sulfate proteoglycans such as brevican, which are suggested to stabilize synapses by their inhibitory effect on structural plasticity, must be remodelled to allow for structural and molecular changes during conditions of homeostatic plasticity. We found a high abundance of cleaved brevican fragments throughout the hippocampus and cortex and in neuronal cultures, with the strongest labelling in perineuronal nets on parvalbumin-positive interneurons. Using an antibody specific for a brevican fragment cleaved by the matrix metalloprotease ADAMTS4, we identified the enzyme as the main brevican-processing protease. Interestingly, we found ADAMTS4 largely associated with synapses. After inducing homeostatic plasticity in neuronal cell cultures by prolonged network inactivation, we found increased brevican processing at inhibitory as well as excitatory synapses, which is in line with the ADAMTS4 subcellular localization. Thus, the ECM is remodelled in conditions of homeostatic plasticity, which may liberate synapses to allow for a higher degree of structural plasticity.


PubMed | Ludwig Maximilians University of Munich, University Hospital Magdeburg, Leibniz Institute for Neurobiology Magdeburg and German Center for Neurodegenerative Diseases
Type: | Journal: Brain structure & function | Year: 2016

A new stereotaxic brain atlas of the Mongolian gerbil (Meriones unguiculatus), an important animal model in neurosciences, is presented. It combines high-quality histological material for identification of brain structures with reliable stereotaxic coordinates. The atlas consists of high-resolution images of frontal sections alternately stained for cell bodies (Nissl) and myelinated fibers (Gallyas) of 62 rostro-caudal levels at intervals of 350m. Brain structures were named according to the Paxinos nomenclature for rodents. The accuracy of the stereotaxic coordinate system was improved substantially by comparing and matching the series of histological sections to in vivo brain images of the gerbil obtained by magnetic resonance imaging (MRI). The skull outlines corresponding to the MR images were acquired using X-ray computerized tomography (CT) and were used to establish the relationship between coordinates of brain structures and skull. Landmarks such as lambda, bregma, ear canals and occipital crest can be used to line up skull and brain in standard atlas coordinates. An easily reproducible protocol allows sectioning of experimental brains in the standard frontal plane of the atlas.

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