Consortium

The NPlast consortium consists of four partners from the private and eight partners from the public sector in six European countries. Coordinator is the Leibniz-Institute for Neurobiology (LIN) in Magdeburg, Germany.

consortium  


   LIN - Germany
   Ascenion GmbH   -   Germany
   ENS - France
   ETH Zurich - Switzerland
   FAN gGMBH - Germany
   INSERM - France
   ProBiodrug - Germany
   ReMYND - Belgium
   The University of Edinburg  - UK
   UMCU - The Netherlands
   UniGenf - Switzerland
   UUtrecht - The Netherlands






Leibniz-Institut für Neurobiologie (LIN)

Leibniz-Institut für Neurobiologie (LIN) LIN

Dr. Michael R. Kreutz (coordinator), Prof. Eckart Gundelfinger, Dr. Anna Fejtova, Dr. Renato Frischknecht, Dr. Martin Heine, Prof. Klaus Reymann

The LIN is a non-profit foundation under public law dedicated to learning and memory research. The LIN is a member of the Leibniz Association (WGL) and constitutes a main pillar of the neurosciences in Magdeburg. Using converging approaches, the research at LIN focuses on mechanisms of memory formation at all organizational and functional levels of the brain in conjunction with analysis of behavior. Research in the participating groups is focused on molecular and cellular mechanisms of plasticity and developmental assembly of chemical synapses in the central nervous system.

The spatial and temporal control of neurotransmitter release from presynaptic boutons is of central importance for proper signaling in the neuronal networks. The components cytoskeleton-associated presynaptic cytomatrix functionally regulate and spatially organize the different steps of synaptic vesicle cycle. The Fejtova/Gundelfinger lab focuses on mechanisms underlying the formation, function and plasticity of this presynaptic cytomatrix using molecular and cellular approaches and mouse genetics.

ESR training project 2:
Investigations on the transition from the physiological to the pathophysiological function of
Dr. Fejtova, Prof. Gundelfinger

Objectives: The production of  peptides in the brain correlates with synaptic activity and recent findings suggest that  is an endogenous regulator of presynaptic function. However, our understanding about the molecular mechanism underlying the presynaptic action of  is far from being complete. We propose that  regulates presynaptic efficacy by modulation of signaling cascades leading eventually to functional and molecular remodeling of the presynaptic release apparatus. Based on published findings we will study whether changes of the presynaptic release apparatus occur upon modulation of endogenous  levels, which signaling cascades are involved and how modulation of the extracellular  concentration affects the activity of neuronal networks. The ESR will assess presynaptic functional remodeling by combining electrophysiological and imaging methods, retrospective and in vivo quantitative immunostainings and over-expression strategies to visualize components of presynaptic release apparatus at the active zone and/or to interfere with their function. To investigate the role of  in modulating the activity of neuronal circuits the ESR will record and analyze network activity of neurons grown on multi-electrode arrays to test the emerging hypothesis that  controls (pre-) synaptic homeostasis. (Contact: This email address is being protected from spambots. You need JavaScript enabled to view it.)

Group Dr. Martin Heine: Within the synapse, not only the stochastic opening kinetics but also the position of neurotransmitter release and the density of postsynaptic receptors add a substantial source of variability of synaptic transmission. By using super resolution microscopy (single particle tracking) and electrophysiological methods (patch clamp) we ask the question, how lateral fluctuations in the neuronal membrane and kinetic properties of ion channels may contribute to the computational properties of neuronal cells.

Group Dr. Renato Frischknecht: Chemical synapses are a structural and functional entity composed of a presynaptic terminal and postsynaptic element, but also glial endfeet infiltrating synaptic contact sites and a highly specialized perisynaptic extracellular matrix. In our group we study the influence of extracellular matrix and its degradation on synaptic function using cell-biological and biochemical approaches.

ESR training project 6
Regulation of ambient glutamate by ECM and glutamate transporters
Dr. Frischknecht, Dr. Heine

Objectives: Synaptic contacts are surrounded by extracellular matrix and glial endfeet. Together, these structures limit concentration and resident time of glutamate in the synaptic cleft. This is achieved by limiting diffusion of glutamate in the extracellular space and/or by glutamate uptake into the glial endfeet via glutamate transporters. Malfunction of glial glutamate transporters leads to excitotoxicity and is associated with a number of neurodegenerative diseases such as AD, Huntington’s disease and amyotrophic lateral sclerosis (ALS). Positioning of glial endfeet, availability of glutamate transporters and volume of the extrasynaptic space are critical for the regulation of glutamate concentration and thus for neuronal signaling through synaptic and extra-synaptic neurotransmitter receptors such as the NMDA receptors. The ESR will assess whether the local organization of glutamate transporters is dynamic and can be modulated by the structure and density of the ECM. This will be achieved by exploring the dynamic organization of glutamate transporters at glia endfeets in correlation to the ECM structure and density and by investigations of the functional impact of ambient glutamate on the structure and composition of the ECM via modulation of the local transporter density/activity. The ESR will be trained to employ super resolution microscopy such as PAINT, SPT and STED combined with optogenetic methods to visualize glutamate transporter dynamics and synaptic activity in parallel. (Contact: This email address is being protected from spambots. You need JavaScript enabled to view it.; This email address is being protected from spambots. You need JavaScript enabled to view it.)

 

Research in the Neuroplasticity Group of Michael R. Kreutz is concerned with molecular mechanisms of cellular plasticity including synaptic and homeostatic plasticity as well as plasticity during development and following brain injury. Of particular interest are the molecular dynamics of the postsynaptic density, signaling from synapse to nucleus and how the synaptic control of nuclear gene expression feeds back into the plastic properties of neurons

ESR training project 8
Synapse-to-nucleus communication in AD
Dr. Kreutz, Prof. Reymann

Jacob is a synapto-nulear protein messenger that couples NMDA-receptor activity to CREB mediated gene expression. The Jacob signaling pathway directly influences morphogenesis and stability of dendrites and spines under physiological and pathological conditions. Under pathological conditions, Jacob can induce a shift in the homeostatic equilibrium of synaptic input, a removal of synapses, dendrite retraction and finally cellular degeneration. Published data indicate that administration of  drives Jacob into the nucleus in an NMDA-receptor-dependent manner. We hypothesize that a loss of synapses induced by the increasing control of the Jacob-CREB pathway via the  peptide is a hallmark of AD. The ESR will study the role of Jacob in the synaptic pathology of AD, the molecular mechanisms of the -induced nuclear translocation of Jacob and the functional consequences of this -induced nuclear translocation event. The ESR will employ AD mouse models, Jacob-mutant mice, and primary cultures grown on microelectrode arrays from these animals. Micro-biochemistry, proteomics and molecular biology methods will be used to reveal the molecular identity of the signaling complex that hooks up Jacob to -signaling. (Contact: This email address is being protected from spambots. You need JavaScript enabled to view it.)


Ascenion GmbH

Ascenion GmbH  ASCENION
Dr. Christian Wunsch

Ascenion GmbH advises public life science research institutions in all aspects of intellectual property asset management to ensure that promising scientific findings are identified, secured and brought to market to the benefit of society.
In Germany Ascenion is exclusive partner of 22 life science institutes in the Helmholtz and Leibniz Associations and of the Hannover Medical School, and coordinates technology transfer in the Program of Medical Genome Research (www.genome-marketplace.de). These organizations’ collective IP portfolio comprises more than 700 patented technologies and commercially interesting materials such as antibodies and vectors.
The company will provide the know-how and soft skills for the NPlast consortium to find suitable industrial partners, negotiate licensing and cooperation agreements, and accompany start-ups.

 

 

 

Ecole Normale Supérieure (ENS)

Ecole Normale Supérieure (ENS) IBENS

Insitute de Biologie de l`ENS (IBENS)
Prof. Antoine Triller, Dr. Andrea Doumoulin, Dr. Christian Specht

The Institut de Biologie de l’ENS (IBENS) is part of the École normale supérieure (ENS). ENS is a higher education institution for advanced undergraduate and graduate studies, and a prestigious French research center. It encompasses fourteen teaching and research departments, spanning the main humanities and sciences disciplines. IBENS represents a unique environment fostering excellence in research, the keystone of which is the complete scientific and financial independence of its research groups. IBENS is organized into four sections: Development, Environmental and Evolutionary Genomics, Functional Genomics, and Neuroscience, and is affiliated with both the national agencies CNRS and INSERM.
Multidisciplinary research is a strong point at IBENS and is further reinforced by local collaborations with the outstanding departments of physics, chemistry, mathematics, cognitive studies, and computing science at the ENS. The Neuroscience Section at IBENS comprises 9 groups representing research themes centered on the synapse, yet ranging from molecular and genetic studies of receptor function to network dynamics in behaving animals and theoretical studies.
Education at IBENS offers a BsC of Biology, and a Master of Biology with several possible majors. Also, an international Master programme is offered in Neurosciences (Dual Masters in Brain and Mind Sciences), along with UPMC (Paris) and UCL (London). All group leaders and most PIs and postdocs are involved in academic teaching and give lectures within their field of expertise.

ESR training project 7:
Regulation of Glycine Receptor (GlyR) dynamics during central sensitization in neuropathic pain
Prof. Triller, Dr. Specht

Objectives: PKC-dependent phosphorylation of the GlyR b-subunit (GlyRb) reduces the affinity of the receptor for the protein scaffold at inhibitory synapses. In this way, the rate of GlyR diffusion is increased, causing a reduction in the levels of GlyRs at inhibitory synapses. This regulation probably causes the disinhibition of nociceptive dorsal horn neurons that occurs during central sensitization in neuropathic pain. The recruited PhD student will explore the molecular processes that underlie the regulation of inhibitory synaptic strength and investigate how the modulation of inhibitory neurotransmission is involved in neuropathic pain. We will dissect the signaling pathway that links excitatory glutamatergic function to the reduction of the inhibitory strength in spinal cord neurons and investigate the mechanisms that govern the diffusion and synaptic clustering of GlyRs . To this end, SPT of receptor diffusion, super-resolution imaging of synaptic scaffold proteins, electrophysiological measurements of inhibitory currents and biochemical approaches to study receptor phosphorylation will be used. The recruited PhD student will evaluate the involvement of PKC-dependent regulation of GlyRs during neuropathic pain in vivo, using phosphospecific antibodies and proteomic analyses of the phosphorylation of GlyRs in spinal cord tissue from an animal model of neuropathic pain. Organotypic spinal cord cultures will be developed as an in vitro system in which GlyR diffusion and localization can be studied in a physiological cellular context using dynamic super-resolution imaging. (Contact: This email address is being protected from spambots. You need JavaScript enabled to view it.; This email address is being protected from spambots. You need JavaScript enabled to view it.)

Eidgenössische Technische Hochschule Zürich (ETH)

Eidgenössische Technische Hochschule Zürich (ETH)   IFOR

Institute for Operations Research (IFOR)
Prof. Robert Weismantel, Dr. Utz-Uwe Haus

The Institute for Operations Research (IFOR), part of the Department of Mathematics, is rooted in theoretical research on structural properties in the area of mathematical optimization, in particular discrete optimization, and the design of efficient algorithms. IFOR is shareholder in the Swiss National Supercomputing Centre, giving privileged access to their resources. Our group has established novel applications of logical programming in medicine and cell biology. By collaboration with various groups of neurobiologists, immunologists and cell biologists within Europe IFOR establishes systems biology approaches for the study of the dysfunction of proteins and the analysis and reconstruction of signal transduction processes.

ER training project 3
Representations of associations and implications for synaptic signaling networks
Prof. Weismantel, Dr. Haus

Signaling networks, e.g. those underlying synapto-nuclear signaling and abstract concept analysis are two important areas of application, in which Boolean functions, and more generally, discrete linear systems are essential modeling tools. The set of all solutions to such a system is typically enormously large but still has to be inspected by practicing experts. Hence compact, navigable representations are key for an effective use of such models. Systems biology approaches based on Boolean functions as developed for understanding T-cell receptor signaling by us (Saez-Rodriguez et al., PLoS Comput Biol 2007 3:e163) should be applicable to neuronal signaling pathways within and downstream of the synapse. In this project we will develop rigorous algorithms that allow the consortium to derive alternative compact representations of essential combinations of attributes that explain observed phenomena.  We will study structures of discrete sets that can be used to simplify representations of the set of all solutions to a discrete problem. This is a challenging task since typically the set of all solutions is highly exponential and a-priori not given in a compact form. We will try to obtain a basic understanding of decompositions and identification of substructures in hypergraphs. The results of this work will be applied to various signaling networks relevant for the consortium. (Contact: This email address is being protected from spambots. You need JavaScript enabled to view it.; This email address is being protected from spambots. You need JavaScript enabled to view it.)

FAN gGMBH

Research Institute for Applied Neurosciences (FAN gGmbH) FAN
Prof. Klaus Reymann


FAN founded in 1996, is a privat, non-profit preclinical and clinical contract research company. It focuses on central nervous system drug and target discovery, especially in the fields of neuroprotection and neurorepair. FAN is affiliated with the Leibniz Institute for Neurobiology and the Otto-von-Guericke-University Magdeburg.

Together with its strategic partners of the Magdeburg neuroscience center FAN assists companies in selecting appropriate and innovative in vitro and in vivo test models for effective CNS drug development.

FAN has international renowned expertise in the fields of stroke, dementia and stem cell research and has a broad network with European Biotech and Pharma companies.

In the NPlast consortium FAN will provide functional assays like LTP, network dysfunction etc.

Institut du Fer-à-Moulin (INSERM)

Institut du Fer-à-Moulin (INSERM)
Prof. Jean-Antoine Girault, Dr. Denis Hervé


The Institut du Fer à Moulin (IFM) is a research center devoted to the study of the development and plasticity of the nervous system. The group of Jean-Antoine Girault and Denis Hervé is interested in signal transduction in neurons. Our goal is to identify intracellular signaling mechanisms that underlie brain plasticity leading to long-lasting behavioral alterations.
Our major model of study is the striatum, which plays a crucial role in the control of movements, motivation, formation of habits, and procedural memory, and is involved in major neurological and psychiatric conditions.

ESR training project 9
Role of nuclear DARPP-32 in the long-term plasticity of striatal neurons
Prof. Girault

Objectives: Dopamine controls movement execution, action selection,and incentive learning by regulating the activity and plasticity of corticostriatal transmission. We are interested in elucidating how dopamine and glutamate combine their effects to long-lastingly alter the properties of striatal neurons. We and others have identified several signaling pathways activated downstream from dopamine D1 and glutamate NMDA receptors that can transmit information to the nucleus of striatal neurons and modify transcription and chromatin. The ESR will participate in the study of these pathways and determine their role in striatalfunction. The training will involve in vitro investigations with striatal neurons in culture,biochemical and molecular biology, new methods for purifying population-specific striatal nuclei, two-photon confocal microscopy for live imaging of molecular trafficking and signalingpathways, and use of a variety of mutant mice for addressing specific points in vivo. (Contact: This email address is being protected from spambots. You need JavaScript enabled to view it.)

 

Probiodrug

Probiodrug  probiodrug
Prof. Dr. Hans-Ulrich Demuth

ESR training project 1
N-terminally ragged and modified Aß peptides – generated by multiple proteolytic pathways leading to protein misfolding
Prof. Dr. Hans-Ulrich Demuth

Multiple N-terminally modified Amyloid-ß peptides make up the majority of deposits in Alzheimer’s Disease (AD). The research project aimes to identifiy novel modified A-ß peptides (via peptide purification and Mass-spectrometry) and to clarify the process of formation and modification by uncovering new proteolytic enzymes and catabolic pathways that lead to protein misfolding. Furthermore, the mechanisms by which the targeted peptides are generated in neurons and their effects in synaptic function will be elucidated. The final aim is to identify new therapeutic targets to interfere with in the production of modified A-ß peptides.

(Contact: This email address is being protected from spambots. You need JavaScript enabled to view it. )

 

ReMYND

reMYND reMYND
Dr. Dick Terwel, Dr. Gerard Griffioen, Dr. An Tanghe

reMYND is a Leuven University spin-off company driving the development of disease-modifying treatments against protein misfolding disorders, organized in two independently-managed business units, both with a proven track record of competency.

reMYND’s Scientific Advisors include key opinion leaders in the fields of PD and AD: prof. Luc Buée, prof. Jeffrey Cummings, prof. Bart De Strooper, prof. Wolfgang Oertel and prof. Werner Poewe. Through its academic and industrial network reMYND participates in collaborations worldwide, e.g. through the EU FP7 network (NEURAD). Moreover, reMYND has received numerous grants (including funding by the Michael J. Fox Foundation) supporting reMYND drug development programs.

Over the past years, reMYND’s scientists have built a strong portfolio of and expertise in state-of-the art in-vitro and in-vivo assays. The scope of reMYND’s CRO entails preclinical in-vivo testing of experimental AD therapies using its proprietary transgenic mouse models and involving strong capabilities in all types of compound administration (e.g., oral gavage, intranasal dosing), behavior testing (e.g., Morris Water Maze testing of spatial reference memory, rotarod testing of motoric capabilities) and neuropathological brain analysis via IHC/histological and biochemical read-outs (e.g., different species/conformations of Abeta and Tau, inflammation). reMYND has several unique transgenic Alzheimer mouse models at its disposal, expressing genes that encode clinical alleles of human APP, PS1 and/or TAU. These models are highly valuable for pre-clinical testing of experimental Alzheimer therapies, given that key AD pathological and behavioral effects are modeled in these mice. Over the past years, additional scientists have been hired and trained in the different assays, in good practice regarding our SPF and AAALAC standards for animal health and welfare, in proper study design, data analysis, and statistics; ensuring a steady performance towards our client base.

ESR training project 11
Improving clinical translatability of transgenic AD mouse models

Dr. Terwel, Dr. Griffioen

The objective of the program at reMYND is to better map the connection of the pathological changes seen in reMYND’s AD animal models at different ages with the described disease progression in patients at different stages, in order to increase the translational predictability of the respective AD animal models. To this end, the anticipated PhD-student will be trained in both the performance of established methods and the implementation of new assays, potentially in collaboration with one of the Belgian university labs. Focus of the project will be on the correlation/causality of oligomeric Abeta and Tau pathology, inflammation, synaptic impairment, neuronal death and their impact on cognitive performance in mice, and their link with CSF markers observed in patients. The principal investigator involved in the NPlast consortium, Dr. Dick Terwel, holds a PhD in Neuroscience and has a vast background in AD. Prior to joining reMYND, Dick has been working as Post-doctoral Researcher at the Department of Human Genetics, Experimental Transgenics Group, Leuven University and as Senior Scientist and Lecturer at the Department of Neurology, Division Clinical Neurosciences, University Clinics Bonn. (Contact: This email address is being protected from spambots. You need JavaScript enabled to view it.; for more information see http://www.remynd.com/jobs/78)

 

The University of Edinburgh (UE)

The University of Edinburgh
Prof. Mike Cousin, Prof. Giles Hardingham

Centre for Integrative Physiology, University of Edinburgh:

The Centre for Integrative Physiology (CIP) has the primary focus of examining how gene products control the function of cells, whole tissues and intact organisms. The Centre comprises a critical mass of Principal Investigators who are drawn from different disciplines, spanning fields such as molecular biology, biochemistry, physiology, neuroscience, chemistry, physics and genetics. The CIP has made a considerable investment in cutting edge laser-based imaging technology. It now has world-class facilities for live cell imaging using both confocal and multi-photon microscopy in combination with FLIM as well as a number of high-end wide-field imaging systems, including TRIF. The CIP has expertise in studies of neuronal function and dysfunction and is a founding member of Edinburgh Neuroscience, the mission of which is to integrate basic and clinical research to drive the fundamental genetic, cellular, organ, systems and computational neuroscience underpinning pathogenesis into mechanistic understanding, future diagnostics and therapeutics of important diseases of the nervous system.

The Cousin lab has expertise in the molecular dissection of presynaptic mechanisms that control the recycling of synaptic vesicles, key technologies include live cell fluorescence imaging of both genetic and chemical reporters in primary neurones.

ESR training project 3
Synaptic vesicle biogenesis in activity-dependent bulk endocytosis
Prof. Cousin

Objectives: Activity-dependent bulk endocytosis (ADBE) is the dominant mode of synaptic vesicle (SV) retrieval during high intensity stimulation in central nerve terminals. Thus modulation of this SV endocytosis mode should impact on neurotransmission during learning, memory and/or epileptic seizures. However, there are no tools currently available to probe the function of ADBE in these physiological and pathophysiological events due to a lack of knowledge of molecules involved. We propose that dysfunctional ADBE contributes towards synaptopathies in both learning / memory (AD) and deregulated excitability (epilepsy). The project has two major aims 1) to identify key molecules whose function is specific to ADBE and 2) to use genetic and pharmacological tools directed against these molecules to determine the role of ADBE in neurotransmission. To this end the we will employ a proteomic identification of bulk endosome components, biochemical SV budding assays from purified bulk endosomes, in vitro protein interaction assays, live imaging of SV recycling in primary neuronal cultures using a range of fluorescent dyes or genetic reporters. (Contact: This email address is being protected from spambots. You need JavaScript enabled to view it.)

The Hardingham lab has expertise in the molecular analyses of signaling pathways that control the survival, death and dysfunction of neurons. This includes mechanisms by which neurons regulate the trascription of neuroprotective genes, including those that regulate apoptotic pathways, antioxidant systems, and mitochondrial function (Curr. Op. Neuro. 21, p299). The control of cell fate by Ca2+ signaling is of particular interest, including signaling from the NMDA receptor which has the capcity to promote both survival or death in different physiological scenarios (Nat Rev Neuro 11, p682).

ESR training project 10
Control of neuronal antioxidant defences through synergistic transcriptional changes in neurons and astrocytes
Prof. Hardingham

Objectives: Many acute and chronic neurodegenerative conditions are associated with oxidative stress. However, trials with small molecule antioxidant compounds have met with limited success. Attention is now shifting to understanding how intrinsic neuronal antioxidant defences can be controlled and manipulated for therapeutic benefit, both within the neuron and cell non-autonomously by regulating astrocytic support. Preliminary data shows that mild oxidative stress controls astrocytic responses via a novel transcriptional mechanism, while synaptic NMDAR activity regulates the capacity of neurons to benefit from astrocytic support. We propose that astrocytes and neurons cooperate via novel transcriptional mechanisms to support neuronal antioxidant defences. The project aims 1) to identify novel mechanisms by which astrocytes respond to oxidative stress to produce and secrete precursors of glutathione synthesis and 2) to identify novel mechanisms by which neuronal activity  controls the uptake and utilization of these precursors in order to combat oxidative stress. The ESR will be trained to prepare primary neuronal cultures and astrocyte cultures and to perform transcriptional profiling using next-generation sequencing (mRNA-seq), live cell imaging, as well as biochemical analysis of antioxidant pathways to prove this hypothesis (with TP7, 10, 14). See Bell et al. PNAS 108(1); Curr. Op. Neuro. 21, p299; Leveille et al J Neurosci. 30, p2623. (Contact: This email address is being protected from spambots. You need JavaScript enabled to view it.)

Universitair Medisch Centrum Utrecht (UMCU)

Universitair Medisch Centrum Utrecht (UMCU)  UMC

University Medical Center Utrecht, Department of Neuroscience and Pharmacology, Division Neuroscience
Prof. Dr. Jeroen Pasterkamp

The Institute:

The University Medical Center Utrecht (UMCU) comprises the largest biomedical campus in the Netherlands and is organized in seven major focus areas including Neuroscience. Large shared facilities and expertise exist in the UMCU for clinical and basic neuroscience research. The Departments within the focus area Neuroscience are organized in an internationally renowned neuroscience research institute, the Rudolf Magnus Institute of Neuroscience, to ensure excellent training of graduate students and postdoctoral fellows, and to promote scientific collaboration over a wide range of neuroscience disciplines (e.g. molecular, cellular, genetics, systems). The Department of Neuroscience and Pharmacology is internationally highly regarded and recognized for work on neurodevelopmental processes, mouse and human genetics, and rodent behavior. The Department offers excellent laboratory, tissue culture, mouse and microscopy facilities, as well as IT support. The setting of the Department of Neuroscience and Pharmacology further offers easy access to local infrastructure. The Pasterkamp laboratory is part of the Genomics Center Utrecht (www.genomicscenter.nl) and the Academic Biomedical Center (www.abc.uu.nl) and as a result has full access to all technical platforms of the University of Utrecht and UMC Utrecht (including the Hubrecht Institute of Developmental Biology and Stem Cell Research). Technical platforms include, but are not limited to, facilities for confocal, laser dissection and multiphoton microscopy, protein expression, FACS, proteomics, gene expression (microarray), and mouse transgenesis.

The Lab:

The focus of the Pasterkamp laboratory (www.jeroenpasterkamplab.com) is directed towards understanding 1) the signaling events and molecular mechanisms involved in the formation of neuronal connections during development, and 2) the molecular mechanisms underlying the loss of neuronal connectivity during neurodegeneration. Our investigations concentrate on the developing mouse embryo using an integrated approach involving molecular biology, cell biology, neuroanatomy, (in vivo) functional proteomics, imaging, HC screening, and mouse genetics. Understanding the molecular and cellular basis of neural circuit development will help us to further understand and treat situations of perturbed neuronal connectivity, such as during neurodevelopmental disorders or as a consequence of neural injury or degeneration.

ESR training project 12
Novel mouse genetics approaches for dissecting dopaminergic pathway development and disease
Prof. Dr. Pasterkamp

Dopaminergic neurons in the mesodiencephalon (mdDA neurons) make precise synaptic connections with regions in the forebrain such as the striatum. Because of the functional importance of these axon pathways and their implication in human disease (e.g. in schizophrenia and Parkinson disease), the mechanisms underlying the development and plasticity of mdDA axon connections are of considerable interest. Unfortunately, progress in this field has been hampered by a lack of tools to study and manipulate dopaminergic axons in vivo. The development of unique mouse genetics tools for studying dopaminergic connectivity will deepen our understanding of the anatomical, molecular and cellular basis of dopaminergic pathway development and plasticity. This project is aimed at the generation of BAC and knock-in mouse lines expressing fluorescent proteins, toxins and/or rhodopsins in specific subsets of mdDA neurons (e.g. in the substantia nigra or ventral tegmental area) to 1) map and manipulate mdDA connectivity, 2) establish specific gene expression profiles during development, plasticity and disease, and 3) study molecular mechanisms identified in other research teams. Promoter sequences that direct gene expression to specific subsets of mdDA neurons and on the Cre-lox and Flp-frt systems will be used. Techniques used include state of the art microscopy and optogenetics techniques to map dopaminergic connectivity during development and in mouse models of disease (e.g. MPTP). FACS array will be employed to generate gene expression profiles (mRNAs and microRNAs) for specific subsets of mdDA neurons. (Contact: This email address is being protected from spambots. You need JavaScript enabled to view it.)

 

Université de Genève (UniGe)

Université de Genève (UniGe) UniGe
Prof. Anthony Holtmaat, Prof. Dominique Muller


A main focus in the Department of Basic Neuroscience is on understanding the molecular mechanisms and functional implications of properties of synaptic plasticity. In the context of NPlast, one contribution will be to investigate the possible synaptic alterations present in a mouse model of the 22q11 deletion syndrome.  A key feature of this syndrome in human is the presence of intellectual disability and autistic traits and a high risk of developing schizophrenia. A main goal of this part of the project will be to test the hypothesis that defects in functional and structural forms of synaptic plasticity might underlie the pathogenesis of 22q11 deletion syndrome. A second point of focus will be on the dynamic restructuring of synaptic connectivity under in vivo conditions in the mice neocortex. The hypothesis that will be tested is that the dynamics of synaptic structures as triggered by paradigms of LTP/LTD and experience-dependent plasticity in vivo are impaired in synaptopathies. Studies will be carried out with mutant mice that display synaptic dysfunctions using two-photon scanning microscopy, expression of photoactivatable fluorescent proteins, electrophysiology and calcium imaging. (For more information see homepage of the Hooltmaat lab and the Muller lab)

Universiteit Utrecht (UU)

Universiteit Utrecht (UU)  UU

Prof. Casper Hoogenraad

Cell Biology of the Neuron – Hoogenraad Lab

The primary goal of the Hoogenraad lab is to understand how intracellular protein trafficking underlies neuronal development and function. We particularly focus on the areas of cytoskeleton dynamics, synaptic cargo trafficking and synaptic plasticity. The research in the lab can roughly be divided in three themes:

  • Cytoskeleton dynamics during neurodevelopment and synaptic plasticity
  • Motor proteins and adaptors as regulators of synaptic transport
  • Neuropsychiatric disorders linked to intracellular transport

Our research relies on combining different genetics, biochemistry, molecular, and cellular biology methods in in vitro (neuron cultures), ex vivo (brain slices), and in vivo (mice) systems. In addition we employ immunofluorescent confocal microscopy, high-resolution live cell imaging (spinning disc microscopy and total internal reflection fluorescence microscopy, TIRF) and quantitative analysis using advanced high-resolution microscopy (photo-activated localization microscopy, PALM).

ESR training project 5
External control of synaptic cargo transport

Prof. Hoogenraad

In the Nplast training project we aim to engineer drug- and light inducible motor protein-cargo complexes that in order to control delivery of postsynaptic receptors to dendritic spines and excitatory synapses. We will make use hippocampal slice cultures, high-resolution two-photon laser scanning microscopy and a new trafficking toolbox recently developed in the lab that allows inducible recruitment of exogenous and endogenous molecular motor proteins to drive cargo transport into spines. The assay controls transport in and out of spines during live-cell recordings by adding cell-permeable small molecules that trigger the binding of specific motor proteins to various synaptic cargos, which from then on report the activity of that particular motor.

Contact: Casper Hoogenraad, Faculty of Science, Utrecht University, Utrecht, The Netherlands, www.cellbio.nl, This email address is being protected from spambots. You need JavaScript enabled to view it.