Logo FOR 2419
Funding Period 2016 - 2018

Plasticity versus Stability:

Molecular Mechanisms of Synaptic Strength

Coordinator: Prof. Dr. Matthias Kneussel

Research Unit FOR 2419 funded by the DFG

Contact: Dr. Eva-Maria Suciu, Tel.: +49 (0) 40 7410-55081


FOR 2419 - Seminars

Save the Date

Hamburg, May 6 - 10, 2017

Blankenese Conference and International FOR 2419 Symposium

"Plasticity versus Stability - Information Update, Synaptic Processing and Coding"

Publications of the FOR 2419

Anda, F.C., Madabhushi, R., Rei, D., Meng, J., Graff, J., Durak, O., Meletis, K., Richter, M., Schwanke, B., Mungenast, A., and Tsai, L.H. (2016). Cortical neurons gradually attain a post-mitotic state. Cell Res. 2016 Jun 21. doi: 10.1038/cr.2016.76. [Epub ahead of print]

Kneussel, M., and Hausrat, T.J. (2016). Postsynaptic Neurotransmitter Receptor Reserve Pools for Synaptic Potentiation. Trends Neurosci 39, 170-182.

Kneussel, M (2016) DFG Forschergruppe FOR 2419 „Plastizität versus Stabilität: Molekulare Mechanismen der Synapsenstärke“. Neuroforum 22, 60-61.

Muhia, M., Thies, E., Labonte, D., Ghiretti, A.E., Gromova, K.V., Xompero, F., Lappe-Siefke, C., Hermans-Borgmeyer, I., Kuhl, D., Schweizer, M., Ohana, O., Schwarz, J.R., Holzbaur, E.L., and Kneussel, M. (2016). The Kinesin KIF21B Regulates Microtubule Dynamics and Is Essential for Neuronal Morphology, Synapse Function, and Learning and Memory. Cell Rep 15, 968-977.

Research Foci and Projects

  • Methodological Approaches of FOR 2419
    Methodological Approaches of FOR 2419

    Neuronal networks operate in intricate circuits to regulate cognitive processes such as learning and memory. Individual neurons are highly plastic by forming and retracting synapses in a neuronal activity-dependent manner. At the molecular level, our understanding of synaptic plasticity is still like a peek through and keyhole. Basic research is therefore required to unravel the mechanisms underlying the structural and functional modifiability of synapses in a given network and, in the long-term to fight synaptopathies.

    The DFG Research Unit FOR 2419 combines molecular biology and mouse genetics with network physiology and optogenetic approaches to address the conflict of “plasticity” versus “stability” at neuronal synapses. Since the majority of molecular components at synapses are highly dynamic and undergo rapid turnover, we ask how does a dynamic system of this kind encode stability in neuronal connectivity and ultimately behavior?

    A central question will be to investigate the molecular mechanisms that stabilize or consolidate synaptic structure and function in order for plastic changes to become persistent. To address these questions we combine experts in studying cytoskeleton transport and local synaptic trafficking with experts in neurophysiology, calcium imaging, optogenetics and synapse structure.

    A main goal is to understand the crosstalk between activity- and calcium-dependent processes with the delivery and removal of synaptic components. Combined investigations of synaptic trafficking with optogenetics and physiology creates a powerful interdisciplinary approach that is currently unique across Germany. In the long-term, we aim to take advantage of optogenetic approaches in order to bridge the molecular level of synaptic research with our understanding of temporal network coordination and cognitive performance in intact animals.

    Summary with references (pdf)

  • Research Focus of FOR 2419 Project P1

    Matthias Kneussel, ZMNH Institute for Molecular Neurogenetics

    Delivery of Plasticity-Related Proteins (PRPs) in Synaptic Consolidation

    We will investigate the role of the “tubulin code” in regulating synapse delivery via microtubules, using three newly generated tubulin knock-in mouse lines that carry mutations to abolish polyglutamylation (poly-Glu). Synaptic delivery of AMPA- and NMDA receptors will be assessed by FRAP and live cell imaging in neurons. Optogenetic protocols will help to specifically induce neuronal activity in hippocampal slices. Poly-Glu tubulin will be visualized by EM. We will ask whether altered poly-Glu tubulin affects synaptic plasticity and learning and vice versa whether behavioral training alters poly-Glu patterns along the cytoskeleton.

  • Research Focus of the FOR 2419 Project P1

    Marina Mikhaylova, ZMNH Research Group Neuronal Protein Transport

    Functional Interplay of Microtubule and Actin Motors in Dendritic Compartmentalization

    Dendritic secretory organelles are local supply stations for plasticity-related products. In this project we would like to understand how the interplay between motor proteins allows for controlled cargo delivery, retention or release in response to synaptic activity in dendritic branch compartments. We hypothesize that i) the organelle positioning in dendrites is determined by local organization of the microtubule and actin cytoskeleton and ii) by local synapto-dendritic Ca2+ signals, which can regulate the activity of different motors on the same cargo allowing for controlled coordination of motility. We aim to gain a better understanding of basic molecular mechanisms involved in regulation of synaptic and dendritic transport mediated by different microtubule- and actinassociated motor proteins and to translate these findings to the models of synaptic plasticity.

  • Research Focus of FOR 2419 Project P3

    Wolfgang Wagner, Institute for Molecular Neurogenetics

    Mechanisms of Actomyosin-Dependent Regulation of Postsynaptic Function and Plasticity in Purkinje Cells

    Members of the myosin family of actin-based cytoskeletal motors play crucial roles for synaptic plasticity at excitatory synapses. Two neuronal myosins that remain to be characterized in this respect are myosin XVI and myosin Id. Strikingly, these myosins physically interact with synaptic plasticity key regulators and appear to be genetically associated with psychiatric disorders. We hypothesize that myosin XVI and myosin Id regulate AMPA receptor trafficking and/or the actin cytoskeleton at the postsynaptic side. Our aim is to test this hypothesis and to uncover the function of these myosins in vitro and in vivo using cerebellar Purkinje cells as a model system. We expect to shed new light on the mechanisms of myosin-dependent synaptic plasticity regulation.

  • Research Focus of FOR 2419 Project P4

    Thomas Oertner, ZMNH Institute for Synaptic Physiology

    Impact of Spine Endoplasmic Reticulum on Synaptic Function and Plasticity

    A subset of spines on hippocampal pyramidal cells contains endoplasmic reticulum (ER), either as a single thin tube protruding into the spine or in the form of a differentiated ‘spine apparatus‘. We demonstrated that synapses with ER reduce their strength after activation of mGluRs, but synapses on spines that lack ER do not support this form of long-term depression (Holbro et al., PNAS 2009). We would like to investigate which signals and molecular mechanisms direct ER tubules into specific spines and how much time it takes to assemble a fully fledged spine apparatus. Furthermore, we want to find out how the presence of ER affects synaptic plasticity and structure and long-term stability of the spine.

  • Research Focus of FOR 2419 Project P5

    Froylan Calderon de Anda, ZMNH Research Group Neuronal Development

    The Role of TAO2 in Synapse Formation and Plasticity

    TAO2 is a member of the MAP Kinase Kinase Kinase (MAPKKK) family. In humans, the gene encoding TAO2 is located on chromosome 16p11.2, a region that carries substantial susceptibility to autism spectrum disorders (ASD) and schizophrenia. We demonstrated a novel role for TAO2 in the development of axons and dendrites (Calderon de Anda F. et al., Nat. Neurosci. 2012). In the proposed project, we will test whether TAO2 is a key player of synapse formation and function. To directly test this, we will elucidate: a) whether TAO2 modulates spine formation via actin cytoskeleton / microtubules remodeling, and b) whether TAO2 depletion affects synapse function mediating endoplasmic reticulum (ER) transport into dendritic spines.

  • Research Focus of FOR 2419 Project P6

    Michael Frotscher, ZMNH Institute for Structural Neurobiology

    Structural Plasticity of Hippocampal Mossy Fiber Synapses

    In this project we aim to characterize the molecular and structural changes associated with functional plasticity of identified hippocampal mossy fiber (MF) synapses. We will use high pressure freezing (HPF) for our electron microscopic studies to minimize tissue alteration such as protein denaturation and tissue shrinkage. We will use 2-photon microscopy to monitor the time course of activity-induced structural changes at identified MF synapses. 2-photon microscopy will also be used to record calcium transients in spines postsynaptic to MF boutons as a read-out of synaptic strength.

  • Research Focus of FOR 2419 Project P7

    Christine E. Gee and J. Simon Wiegert, ZMNH Institute for Synaptic Physiology

    Dynamic Rewiring of Hippocampal Circuits Following Synaptic Plasticity

    We propose to study how the lifetime of excitatory synapses is regulated by activity. In organotypic slice cultures of rat hippocampus, we will combine optogenetic induction of long-term plasticity (LTP, LTD) at identified synapses with optogenetic modulation of synaptic activity during the following days. Controlling the activity of identified neurons allows us to investigate the long-term consequences of synaptic plasticity rules on the network level. Do new synapses form at random or do they preferentially form between best synchronized pre- and postsynaptic neuronal populations? The ultimate goal is to understand the connection between functional and structural synaptic plasticity and to decipher the rules of activity-dependent brain wiring.

Supervision and Training for Doctoral Students of FOR 2419

Each doctoral student involved in a project of the FOR 2419 is tutored by a principal investigator of the FOR 2419. He or she concludes a supervision agreement with this main supervisor and two mentors; one of the mentors is another principal investigator of the FOR 2419. The supervision agreement specifies the rights and duties of the persons involved such as a yearly thesis committee meeting in which the doctoral student presents a progress report on the dissertation to the main supervisor and the mentors. Successfully completed doctoral studies will lead to the award of a doctoral degree in conformity with the regulations of the Faculty of Mathematics, Informatics and Natural Sciences (MIN Faculty) or the Faculty of Medicine of Universität Hamburg.

This supervision concept is part of the ZMNH PhD Program which aims at ensuring the best possible supervision and support of doctoral students as well as a high quality of interdisciplinary academic education. Furthermore, two ombudspersons and two PhD student representatives, annually elected by the ZMNH Scientists’ Conference, support doctoral students’ activities at the ZMNH. For example, the ZMNH Doctoral Students’ Journal Club meets regularly and there are monthly Internal PhD-Seminars for discussing own research findings.

In addition to the support and supervision of doctoral students’ thesis research, the attendance of ZMNH-Seminars, seminars of the Hamburg Center of NeuroScience and of the lectures and research methods courses of the ZMNH-based Graduate Program in Molecular Biology (ASMB) is offered. Moreover, the doctoral students may join interdisciplinary, research methods and academic key skill courses offered by the Faculty of Medicine, the MIN Faculty as well as the Career Center of Universität Hamburg.