Research Unit FOR 2419 funded by German Research Foundation (Deutsche Forschungsgemeinschaft, DFG)

Plasticity versus Stability - Molecular Mechanisms of Synaptic Strength

Speaker: Prof. Dr. Matthias Kneussel

Coordinator: Jennifer Radwitz (jennifer.radwitz@zmnh.uni-hamburg.de)

Research Focus

Dynamic changes in synaptic strength, termed synaptic plasticity, are a cellular mechanism for the dynamic adaptation of neuronal networks that is widely recognized to underlie cognitive functions such as learning and memory. In six projects, FOR 2419 scientists at ZMNH and the Universities of Hamburg and Mainz investigate different aspects of activity-dependent structural and functional synaptic plasticity at the molecular and cellular level.

FOR Symposium

International FOR 2419 Symposium

The Dynamic Synapse - Molecular and Cellular Mechanisms of Synaptic Strength

April 20 - 22, 2022

Further FOR 2419 Events and Research Highlights

  • Past FOR 2419 - Seminars and Conferences

    Prof. Fritjof Helmchen , Zürich Neocortical signal flow in sensory discrimination tasks involving short-term memory

    Prof. Tommaso Patriarchi , Zurich Genetically encoded tools for high-resolution in vivo imaging of dopamine dynamics

    Prof. Wanda Kukulski , Bern The supramolecular landscape of growing humann axons

    Prof. Amparo Acker-Palmer , Frankfurt Wiring neuronal and vascular networks

    Prof. Michael Tamkun , Fort Collins, CO Neuronal cell biology of Kv2.1-induced endoplasmic reticulum/plasma membrane contact sites

    Prof. Olivia Masseck , Bremen Illuminating the seratonergic system

    Prof. Patrik Verstreken , Leuven The cellular basis of Parkinson's disease

    Dr. Michael Lippert , Magdeburg Functional imaging of brain stimulation reward

    Prof. Antonia Roll-Mecak , Bethesda, MD Microtubule dynamics: not only at the tiips

    Dr. Johannes Letzkus , Frankfurt/Main Processing of top-down information in mouse and human neocortex

    Dr.. Marie-Jo Moutin , Grenoble Tubulin detyrosination by vasohibin-SVBP enzyme complex is crucial for neuron and brain

    Prof. Christiane Wrann , Boston, MA Molecular mediators of the cognitive benefits of exercise

    Dr. Johannes Kohl , London Investigating the neural circuits underlying instinctive behaviors

    Dr. Nelson Totah , Tübingen The roles of attention, errors, and noradrenaline during learning in an electrophysiology-compatible rodent set-shifting task

    Prof. Peter W. Baas , Philadelphia Hereditary Spastic Paraplegia: gain-of-function mechanisms revealed by new transgenic mouse

    Dr. Tomomi Shimogori , RIKEN Center for Brain Science, Japan Activity dependent Btbd3 protein dynamics for selective dendrite morphogenesis in developing neuron

    Dr. Ernesto Ciabatti , Cambridge Life-long manipulation of neural networks: from basic to translational research

    Dr. Christian Lohmann , Amsterdam How spontaneous activity wires the developing brain prior to experience

    Dr. Karin Dumstrei , Heidelberg Behind the scenes of scientific publishing

    Prof. Dr. Stefan Hallermann , Leipzig Action potential dynamics in small cortical nerve terminal revealed by direct patch clamp recordings

    Prof. Ryuichi Shigemoto , Klosterneuburg Short- and long-term synaptic plasticity in cerebeller motor learning

    Prof. Christiane Wrann , Boston Molecular mechanisms of exercise: potential therapeutic role for FNDC5/irisin

    Prof. Alain Chédotal , Paris Development and evolution of commissural circuits

    Prof. Brian McCabe , Lausanne Mechanisms and maladies of motor circuits and synapses

    Prof. Dr. Valentin Stein , Bonn Neddylation of synaptic proteins

    Univ.-Prof. Mag. Dr. Thomas Klausberger , Vienna Prefronal circuits for decision-making

    Prof. Dr. Yimin Zou , San Diego: Breaking symmetry - polarity signaling in axon guidance and synapse formation

    Dr. Ofer Yizhar , Rehovot Optogenetic manipulation of axonal terminals: the good, the bad, and the surprising

    "Uncovering Synaptic Plasticity: From Molecules to Memory" International FOR 2419 Symposium 2018: Scientific Program (pdf 301 KB)

    Dr. Beatriz Rebollo , Barcelona Synaptic and non-synaptic propagation of slow waves and their modulation by endogenous electric fields

    Prof. Dr. Sabine Lévi , Paris Tuning of synaptic inhibition by the second messenger Cl-

    Prof. Dr. Martijn Schonewille, Rotterdam Unraveling the cerebellar cortex: module-related differences in activity and plasticity

    Prof. Dr. Claudia Bagni , Lausanne The molecular basis of brain wiring and social behaviour

    Dr. Andrea Barberis , Genova Spatial regulation of coordinated excitatory and inhibitory synaptic plasticity

    Prof. Dr. Wieland Huttner , Dresden Neural stem and progenitor cells and neocortex expansion in development and evolution

    Prof. Dr. Siegrid Löwel , Göttingen The dynamic architecture of the adult visual cortex or how can I keep my brain young?

    Prof. Dr. Tobias Moser , Göttingen How hearing happens: molecular physiology and optogenetic restoration

    Prof. Dr. Anthony Holtmaat , Geneva Facilitation of synaptic plasticity in the mouse somatosensory cortex by paralemniscal circuits

    Dr. Frédéric Gambino , Bordeaux Dendritic mechanisms for associative learning in behaving animals

    Dr. Rajiv Mishra , Klosterneuburg Cellular mechanisms of learning and memory: synaptic plasticity at CA3-CA3 synapses

    Prof. Imre Vida , Berlin: Inhibiting inhibition: fast and slow inhibitory interactions among hippocampal GABAergic interneurons

    Dr. Benjamin Rost , Berlin: Optogenetics at the presynaptic terminal

    Prof. Victor Tarabykin , Berlin: Molecular control of the cortical development

    Prof. Dr. Britta Qualmann , Jena: Actin nucleation and membrane remodelling in neuromorphogenesis and synaptic plasticity

    Dr. Nathalie Sans , Bordeaux: Planar cell polarity proteins and molecular mechanisms regulating exitatory synapses

    Prof. Guus Smit, Amsterdam: Dissecting the role of auxiliary subunits in the regulation of AMPA-type glutamate receptors

    Prof. Martin Korte, Braunschweig: Losing the Balance between Plasticity and Stability: Neuroinflammation and Neurodegeneration

    Dr. Martin Fuhrmann, Bonn: Cellular and synaptic correlates of learning and memory

    Prof. Johann H. Brandstätter, Erlangen: Adaptation at a sensory synapse - the role of complexins

    The 37th Blankenese Conference 2017 "Synaptic Plasticity versus Stability: Information Uptake, Processing and Coding" covered the focus of FOR 2419 complemented by aspects of the plasticity of cellular circuits in the olfactory and taste systems to illuminate the role of synapses in information processing in the central and peripheral nervous system. Scientific Program (pdf) Abstracts (pdf)

  • Publications

    2021

    Kneussel M, Sánchez-Rodríguez N, Mischak M, Heisler FF (2021) Dynein and muskelin control myosin VI delivery towards the neuronal nucleus. iScience (in press)

    Perez-Alvarez A, Huhn F, Dürst CD, Franzelin A, Lamothe-Molina PJ, Oertner TG (2021) Freeze-frame imaging of dendritic calcium signals with TubuTag. Front Mol Neurosci 14:635820. PubMed

    2020

    Bayraktar G, Yuanxiang P, Confettura AD, Gomes GM, Raza SA, Stork O, Tajima S, Suetake I, Karpova A, Yildirim F, Kreutz MR (2020) Synaptic control of DNA methylation involves activity-dependent degradation of DNMT3A1 in the nucleus. Neuropsychopharmacology 45:2120-2130. PubMed

    Bucher M, Fanutza T, Mikhaylova M (2020) Cytoskeletal makeup of the synapse: Shaft versus spine. Cytoskeleton (Hoboken). 77:55-64. PubMed

    Bucher M, Niebling S, Han Y, Molodenskiy D, Kreienkamp HJ, Svergun D, Kim E, Kostyukova AS, Kreutz MR, Mikhaylova M (2020) Autism associated SHANK3 missense point mutations impact conformational fluctuations and protein turnover at synapses. bioRxiv 2020.12.31.424970.

    Hausrat TJ, Radwitz J, Lombino F, Breiden P, Kneussel M (2020) Alpha- and beta-tubulin isotypes are differentially expressed during brain development. Dev Neurobiol. 2020 Apr 15. doi: 10.1002/dneu. 22745. Online ahead of print. PubMed

    Hu C, Kanellopoulos AK, Richter M, Petersen M, Konietzny A, Tenedini FM, Hoyer N, Cheng L, Poon CLC, Harvey KF, Windhorst S, Parrish JZ, Mikhaylova M, Bagni C, Calderon de Anda F, Soba P (2020) Conserved Tao kinase activity regulates dendritic arborization, cytoskeletal dynamics, and sensory function in Drosophila. J Neurosci 40:1819-1833. PubMed

    Konietzny A, Grendel J, Hertrich N, Dekkers DHW, Demmers JAA, Mikhaylova M (2020) Synaptic anchoring of the endoplasmic reticulum depends on myosin V and caldendrin activity. bioRxiv 2020.08.14.250746.

    Meka DP, Scharrenberg R, Calderon de Anda F (2020) Emerging roles of the centrosome in neuronal development. Cytoskeleton (Hoboken) 77: 84-96. PubMed

    Lopes AT, Hausrat TJ, Heisler FF, Gromova KV, Lombino FL, Fischer T, Ruschkies L, Breiden P, Thies E, Hermans-Borgmeyer I, Schweizer M, Schwarz JR, Lohr C, Kneussel M (2020) Spastin depletion increases tubulin polyglutamylation and impairs kinesin-mediated neuronal transport, leading to working and associative memory deficits. PLoS Biol 18:e3000820. PubMed

    Pahle J, Muhia M, Wagener RJ, Tippmann A, Bock HH, Graw J, Herz J, Staiger JF, Drakew A, Kneussel M, Rune GM, Frotscher M, Brunne B (2019) Selective inactivation of Reelin in inhibitory interneurons leads to subtle changes in the dentate gyrus but leaves cortical layering and behavior unaffected. Cereb Cortex 30:1688-1707. PubMed

    Pelucchi S, Vandermeulen L, Pizzamiglio L, Aksan B, Yan J, Konietzny A, Bonomi E, Borroni B, Padovani A, Rust MB, Di Marino D, Mikhaylova M, Mauceri D, Antonucci F, Edefonti V, Gardoni F, Di Luca M, Marcello E (2020) Cyclase-associated protein 2 dimerization regulates cofilin in synaptic plasticity and Alzheimer’s disease. Brain commun 2:fcaa086. PubMed

    Perez-Alvarez A*, Fearey BC*, O'Toole RJ, Yang W, Arganda-Carreras I, Lamothe-Molina PJ, Moeyaert B, Mohr MA, Panzera LC, Schulze C, Schreiter ER, Wiegert JS, Gee CE, Hoppa MB, Oertner TG (2020) Freeze-frame imaging of synaptic activity using SynTagMA. Nature Comm 11:2464 *equal contribution PubMed

    Perez-Alvarez A, Yin S, Schulze C, Hammer JA, Wagner W, Oertner TG (2020) Endoplasmic reticulum visits highly active spines and prevents runaway potentiation of synapses. Nat Commun 11:5083. Pubmed

    2019

    Andres-Alonso M, Ammar MR, Butnaru I, Gomes GM, Sanhueza GA, Raman R, Yuanxiang PA, Borgmeyer M, Lopez-Rojas J, Raza SA, Brice N, Hausrat TJ, Macharadze T, Diaz-Gonzalez S, Carlton M, Failla AV, Stork O, Schweizer M, Gundelfinger ED, Kneussel M, Spilker C, Karpova A, Kreutz MR (2019) SIPA1L2 controls trafficking and local signaling of TrkB-containing amphisomes at presynaptic terminals. Nat Commun 10: 5448. PubMed

    Anisimova M, van Bommel Bas, Wiegert JS, Mikhaylova M, Oertner TG, Gee CE (2019) Long vs short-term synaptic learning rules after optogenetic spike-timing-dependent plasticity. bioRxiv 863365; doi: https://doi.org/10.1101/863365

    Binder S, Mölle M, Lippert M, Bruder R, Aksamaz S, Ohl F, Wiegert JS, Marshall L (2019) Monosynaptic hippocampal-prefrontal projections contribute to spatial memory consolidation in mice. J Neurosci 39:6978-6991. PubMed

    Dürst CD, Wiegert JS, Helassa N, Kerruth S, Coates C, Schulze C, Geeves MA, Török K, Oertner TG (2019) High-speed imaging of glutamate release with genetically encoded sensors. Nature Protocols 14:1401-1424. PubMed

    Fricke S, Metzdorf K, Ohm M, Haak S, Heine M, Korte M, Zagrebelsky M (2019) Fast Regulation of GABAAR diffusion dynamics by Nogo-A signaling. Cell Rep 29:671-684.e6. PubMed

    Gao X, Grendel J, Muhia M, Castro-Gomez S, Süsens U, Isbrandt D, Kneussel M, Kuhl D, Ohana O (2019) Disturbed prefrontal cortex activity in the absence of Schizophrenia-like behavioral dysfunction in Arc/Arg3.1 deficient mice. J Neurosci 39:8149-8163. PubMed

    Konietzny A, Gonzalez-Gallego J, Bar J, Perez-Alvarez A, Drakew A, Demmers JAA, Dekkers DHW, Hammer JA, 3rd, Frotscher M, Oertner TG, Wagner W, Kneussel M, Mikhaylova M (2019) Myosin V regulates synaptopodin clustering and localization in the dendrites of hippocampal neurons. J Cell Sci 132:jcs230177. PubMed

    Lombino FL, Muhia M, Lopez-Rojas J, Brill MS, Thies E, Ruschkies L, Lutz D, Richter M, Hausrat TJ, Lopes AT, McNally FJ, Hermans-Borgmeyer I, Dunleavy JEM, Hoffmeister-Ullerich S, Frotscher M, Misgeld T, Kreutz MR, de Anda FC, Kneussel M (2019) The microtubule severing protein katanin regulates proliferation of neuronal progenitors in embryonic and adult neurogenesis. Sci Rep 9:15940. PubMed

    Meka DP, Scharrenberg R, Zhao B, Koenig T, Schaefer I, Schwanke B, Kobler O, Klykov S, Richter M, Eggert D, Windhorst S, Dotti CG, Kreutz MR, Mikhaylova M, Calderon de Anda F (2019) Radial F-actin organization during early neuronal development. EMBO Rep 20:e47743. PubMed

    Oppermann J, Fischer P, Silapetere A, Liepe B, Rodriguez-Rozada S, Flores-Uribe J, Peter E, Keidel A, Vierock J, Kaufmann J, Broser M, Luck M, Bartl F, Hildebrandt P, Wiegert JS, Béjà O, Hegemann P, Wietek J (2019) MerMAIDs: a family of metagenomically discovered marine anion-conducting and intensely desensitizing channelrhodopsins. Nat Commun 10:3315. PubMed

    Richter M, Murtaza N, Scharrenberg R, White S, Johanns O, Walker S, Yuen RK, Schwanke B, Bedürftig B, Henis M, Scharf S, Kraus V, Dörk R, Hellmann J, Lindenmaier Z, Ellegood J, Hartung H, Kwan V, Sedlacik J, Fiehler J, Schweizer M, Lerch JP, Hanganu-Opatz I, Morellini F, Scherer SW, Singh KK, Calderon de Anda F (2019) Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling. Mol Psychiatry 24:1329-1350. PubMed

    Roesler MK, Lombino FL, Freitag S, Schweizer M, Hermans-Borgmeyer I, Schwarz JR, Kneussel M, Wagner W (2019) Myosin XVI Regulates Actin Cytoskeleton Dynamics in Dendritic Spines of Purkinje Cells and Affects Presynaptic Organization. Front Cell Neurosci 13:330. PubMed

    van Bommel B, Konietzny A, Kobler O, Bär J, Mikhaylova M (2019) F-actin patches associated with glutamatergic synapses control positioning of dendritic lysosomes. EMBO J. 2019 Jun 27:e101183. PubMed

    Wagner W, Lippmann K, Heisler FF, Gromova KV, Lombino FL, Roesler MK, Pechmann Y, Hornig S, Schweizer M, Polo S, Schwarz JR, Eilers J, Kneussel M (2019) Myosin VI drives clathrin-mediated AMPA receptor endocytosis to facilitate cerebellar long-term depression. Cell Rep 28:11-20.e9. PubMed

    2018

    Calderon de Anda F, Gaertner A (2018) Editorial: Neuronal Polarity: Establishment and Maintenance. Front Cell Neurosci 12:137. PubMed

    Cox RL, Calderon de Anda F, Mangoubi T, Yoshii A (2018) Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain. Front Mol Neurosci 11:409. PubMed

    Gromova KV, Muhia M, Rothammer N, Gee, CE, Thies E, Schaefer I, Kress S, Kilimann MW, Shevchuk O, Oertner TG, Kneussel M (2018) Neurobeachin and the kinesin KIF21B are critical for endocytic recycling of NMDA receptors and regulate social behavior. Cell Reports 23:2705-2717. PubMed

    Heisler FF, Pechmann Y, Wieser I, Altmeppen HC, Veenendaal L, Muhia M, Schweizer M, Glatzel M, Krasemann S, Kneussel M (2018) Muskelin coordinates PrPC 1 lysosome versus exosome targeting and impacts prion disease progression. Neuron 99:1155-1169.e9 PubMed

    Helassa N, Dürst CD, Coates C, Arif U, Schulze C, Wiegert JS, Geeves M, Oertner TG, Török K (2018) Ultrafast glutamate sensors resolve high-frequency release at Schaffer collateral synapses. Proc Natl Acad Sci USA 115:5594-5599. PubMed

    Mikhaylova M*, Bar J, van Bommel B, Schatzle P, YuanXiang P, Raman R, Hradsky J, Konietzny A, Loktionov EY, Reddy PP, Lopez-Rojas J, Spilker C, Kobler O, Raza SA, Stork O, Hoogenraad CC, Kreutz MR* (2018) Caldendrin directly couples postsynaptic calcium signals to actin remodeling in dendritic spines. Neuron 97:1110-1125 e14. *shared correspondence PubMed

    Interview of Mikhaylova M in LATEST THINKING, an independent Open Access Video Journal
    How is Cross-Talk Between Calcium and Actin Cytoskeleton Involved in Memory Formation?

    Moeyaert B, Holt G, Madangopal R, Perez-Alvarez A, Fearey BC, Trojanowski NF, Ledderose J, Zolnik TA, Das A, Patel D, Brown TA, Sachdev RNS, Eickholt BJ, Larkum ME, Turrigiano GG, Dana H, Gee CE, Oertner TG, Hope BT, Schreiter ER (2018) Improved methods for marking active neuron populations. Nat Commun 9:4440. PubMed

    Scheib U, Broser M, Constantin OM, Yang S, Gao S, Mukherjee S, Stehfest K, Nagel G, Gee CE*, Hegemann P* (2018) Rhodopsin-cyclases for photocontrol of cGMP/cAMP and 2.3 Å structure of the adenylyl cyclase domain. Nat Commun 9:2046 DOI: 10.1038/s41467-018-04428-w *equal contribution PubMed

    Seipold L, Altmeppen H, Koudelka T, Tholey A, Kasparek P, Sedlacek R, Schweizer M, Bar J, Mikhaylova M, Glatzel M, Saftig P (2018) In vivo regulation of the A disintegrin and metalloproteinase 10 (ADAM10) by the tetraspanin 15. Cell Mol Life Sci 75:3251-3267. PubMed

    Shehabeldin R, Lutz D, Karsak M, Frotscher M, Krieglstein K, Sharaf A (2018) Reelin controls the positioning of brainstem serotonergic raphe neurons. PloS One 13. PubMed

    Shehabeldin R et al: (2019) Correction: Reelin controls the positioning of brainstem serotonergic raphe neurons. PloS One 14:e0211849. PubMed

    Stanelle-Bertram S, Walendy-Gnirß K, Speiseder T, Thiele S, Asante IA, Dreier C, Kouassi NM, Preuß A, Pilnitz-Stolze G, Müller U, Thanisch S, Richter M, Scharrenberg R, Kraus V, Dörk R, Schau L, Herder V, Gerhauser I, Pfankuche VM, Käufer C, Waltl I, Moraes T, Sellau J, Hoenow S, Schmidt-Chanasit J, Jansen S, Schattling B, Ittrich H, Bartsch U, Renné T, Bartenschlager R, Arck P, Cadar D, Friese MA, Vapalahti O, Lotter H, Benites S, Rolling L, Gabriel M, Baumgärtner W, Morellini F, Hölter SM, Amarie O, Fuchs H, Hrabe de Angelis M, Löscher W, Calderon de Anda F, Gabriel G (2018) Male offspring born to mildly ZIKV-infected mice are at risk of developing neurocognitive disorders in adulthood. Nat Microbiol 3:1161-1174 PubMed

    Vulinovic F, Krajka V, Hausrat TJ, Seibler P, Alvarez-Fischer D, Park J-S, Kumar KR, Sue CM, Lohmann K, Kneussel M, Klein C, Rakovic A (2018) Motor protein binding and mitochondrial transport are altered by pathogenic TUBB4A variants. Hum Mutat 39:1901-1915 PubMed

    Wiegert JS, Pulin M, Gee CE, Oertner TG (2018) The fate of hippocampal synapses depends on the sequence of plasticity-inducing events. Elife 7:e39151 PubMed

    2017

    Bender RA, Zhou L, Vierk R, Brandt N, Keller A, Gee CE, Schafer MK, Rune GM (2017) Sex-dependent regulation of aromatase-mediated synaptic plasticity in the basolateral amygdala. J Neurosci 37:1532-1545. PubMed

    Bitzenhofer SH, Ahlbeck J, Wolff A, Wiegert JS, Gee CE, Oertner TG, Hanganu-Opatz IL (2017) Layer-specific optogenetic activation of pyramidal neurons causes beta-gamma entrainment of neonatal networks. Nat Commun 8:14563. PubMed

    Drakew A, Maier U, Tippmann A, Frotscher M (2017) Single synapses control mossy cell firing. bioRxiv

    Frotscher M, Zhao S, Wang S, Chai X (2017) Reelin signaling inactivates cofilin to stabilize the cytoskeleton of migrating cortical neurons. Front Cell Neurosci 11:148. PubMed

    Haumann I, Junghans D, Anstötz M, Frotscher M (2017) Presynaptic localization of GluK5 in rod photoreceptors suggests a novel function in the mammalian retina. PloS ONE 12(2):e0172967. PubMed

    Heinz L, Muhs S, Schiewek J, Grüb S, Nalaskowski M, Lin Y-N, Wikman H, Oliveira-Ferrer L, Lange T, Wellbrok J, Konietzny A, Mikhaylova M, Windhorst S (2017) Strong fascin expression promotes metastasis independent of its F-actin bundling activity. Oncotarget 8:110077-110091. PubMed

    Konietzny A, Bär J, Mikhaylova M (2017) Dendritic actin cytoskeleton: structure, functions, and regulations. Front Cell Neurosci 11:147. PubMed

    Maric HM, Hausrat TJ, Neubert F, Dalby NO, Doose S, Sauer M, Kneussel M, Stromgaard K (2017) Gephyrin-binding peptides visualize postsynaptic sites and modulate neurotransmission. Nat Chem Biol 13:153-160. PubMed

    Wiegert JS, Mahn M, Prigge M, Printz Y, Yizhar O (2017) Silencing neurons: tools, applications and experimental constraints. Neuron 95:504-529. PubMed

    Wietek J, Rodriguez-Rozada S, Tutas J, Tenedini F, Grimm C, Oertner TG, Soba P, Hegemann P, Wiegert JS (2017) Anion-conducting channelrhodopsins with tuned spectra and modified kinetics engineered for optogenetic manipulation of behavior. Sci Rep 7:14957. PubMed

    Zhao B, Meka DP, Scharrenberg R, König T, Schwanke B, Kobler O, Windhorst S, Kreutz MR, Mikhaylova M, Calderon de Anda F (2017) Microtubules modulate F-actin dynamics during neuronal polarization. Sci Rep 7:9583. PubMed

    2016

    Bär J, Kobler O, van Bommel B, Mikhaylova M (2016) Periodic F-actin structures shape the neck of dendritic spines. Sci Rep 6:37136. PubMed

    Brill MS*, Kleele T*, Ruschkies L*, Wang M, Marahori NA, Reuter MS, Hausrat TJ, Weigand E, Fisher M, Ahles A, Engelhardt S, Bishop DL, Kneussel M, Misgeld T (2016) Branch-specific microtubule destabilization mediates axon branch loss during neuromuscular synapse elimination. Neuron 92:845-856. *Co-first authors PubMed

    Calderon de Anda F, Madabhushi R, Rei D, Meng J, Graff J, Durak O, Meletis K, Richter M, Schwanke B, Mungenast A, Tsai LH (2016) Cortical neurons gradually attain a post-mitotic state. Cell Res 26:1033-1047. PubMed

    Chai X, Frotscher M (2016) How does Reelin signaling regulate the neuronal cytoskeleton during migration? Neurogenesis 3:e1242455. PubMed

    Chai X, Zhao S, Fan L, Zhang W, Lu X, Shao H, Wang S, Song L, Failla AV, Zobiak B, Mannherz HG, Frotscher M (2016) Reelin and cofilin cooperate during the migration of cortical neurons: a quantitative morphological analysis. Development 143:1029-1040. PubMed

    Guzman SJ, Schlogl A, Frotscher M, Jonas P (2016) Synaptic mechanisms of pattern completion in the hippocampal CA3 network. Science 353:1117-1123. PubMed

    Kneussel M, Hausrat TJ (2016). Postsynaptic neurotransmitter receptor reserve pools for synaptic potentiation. Trends Neurosci 39, 170-182. PubMed

    Kwan V, Meka DP, White SH, Hung CL, Holzapfel NT, Walker S, Murtaza N, Unda BK, Schwanke B, Yuen RK, Habing K, Milsom C, Hope KJ, Truant R, Scherer SW, Calderon de Anda F, Singh KK (2016) DIXDC1 phosphorylation and control of dendritic morphology are impaired by rare genetic variants. Cell Rep 17:1892-1904. PubMed

    Muhia M, Thies E, Labonte D, Ghiretti AE, Gromova KV, Xompero F, Lappe-Siefke C, Hermans-Borgmeyer I, Kuhl D, Schweizer M, Ohana O, Schwarz JR, Holzbaur EL, 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. PubMed

    Takahashi N, Oertner TG, Hegemann P, Larkum ME (2016) Active cortical dendrites modulate perception. Science 354:1587-1590. PubMed

    van Bommel B, Mikhaylova M (2016) Talking to the neighbours: The molecular and physiological mechanisms of clustered synaptic plasticity. Neurosci Biobehav Rev 71:352-361. PubMed

  • DFG approved a second funding period of FOR 2419

    The DFG approved 2.6 million Euros for the Research Unit FOR 2419 “Plasticity versus Stability: Molecular Mechanisms of Synaptic Strength” in the years 2019 to 2021. Six projects of researchers from ZMNH and the universities in Mainz and Hamburg are funded. Spokesperson is Prof. Dr. Matthias Kneussel.

    Press release of Deutsche Forschungsgemeinschaft (DFG) (in German)

    Press release of UKE (pdf) (in German)

    Project details on GEPRIS website of DFG (in English)

    December 7, 2018

    New potential therapeutic target for AutismSpectrum disorder

    Intensive research under the direction of Dr. Froylan Calderon de Anda, Research Group Neuronal Development at the Center for Molecular Neurobiology (ZMNH) of the University Medical Center Hamburg-Eppendorf (UKE), revealed that mutations in the TAO2 gene leading to a reduced gene activity result in an increased risk for autism spectrum disorders (ASDs). The scientists identified RhoA signaling as a mediator of TAOK2-dependent synaptic development that has the potential for a new therapeutic target for ASDs.

    Reference: Richter et al., Altered TAOK2 activity causes autism-related neurodevelopmental 3 and cognitive abnormalities through RhoA signaling. Molecular Psychiatry, 2018, DOI: https://doi.org/10.1038/s41380-018-0025-5

    Press release of UKE (in German)

    Resonance in international press

    SPECTRUM NEWS and Newsweek En ESPANOL

    April 4, 2018

    Preview of Mikhaylova et al. (2018) Neuron 97:1110-1125 e11

    Open Up to Make New Contacts: Caldendrin Senses Postsynaptic Calcium Influx to Dynamically Organize Dendritic Spines

    by Andrew Coleman and Thomas Biederer

    Preview of the article

    Mikhaylova M*, Bär J, van Bommel B, Schätzle P, YuanXiang PY, Raman R, Hradsky J, Konietzny A, Loktionov EY, Reddy PP, Lopez-Rojas J, Spilker C, Kobler O, Raza SA, Stork O, Hoogenraad CC, Kreutz MR* (2018). Caldendrin directly couples postsynaptic calcium signals to actin-remodeling in dendritic spines. Neuron 97:1110-1125 e1114.
    *shared correspondenc

    March 7, 2018

    FOR 2419 scientist was awarded an ERC Starting Grant

    Dr. J. Simon Wiegert from the ZMNH Institute for Synaptic Physiology was awarded an ERC Starting Grant from the European Research Council (ERC) for his project “LIFE synapses – Long-term Investigation of Functional Excitatory Synapses: Linking Plasticity, Network Wiring and Memory Storage”. The project aims at deciphering the role of synapses for information processing and memory storage in the mammalian brain by combining state-of-the-art imaging techniques such as 2-photon microscopy with latest optogenetic approaches. The grant amounts to € 1.5 million for a period of five years.

    Press release of the University Medical Center Hamburg-Eppendorf (in German, pdf)

    October 7, 2016

    DFG Research Unit FOR 2419 "Plasticity versus Stability"

    The German Research Foundation (DFG) has granted 2.5 million EUR for the Research Unit FOR 2419 "Plasticity versus Stability: Molecular Mechanisms of Synaptic Strength" which focusses on the longstanding question of synapse and network plasticity. Seven research projects of ZMNH researchers are involved and coordinated by Prof. Dr. Matthias Kneussel.

    Press release of the DFG (in German)

    October 1st, 2015

  • NBEA and KIF21B regulate synaptic NMDA receptor recycling
    NBEA and KIF21B regulate synaptic NMDA receptor recycling

    P1

    Matthias Kneussel, ZMNH Institute of Molecular Neurogenetics

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

    The delivery of PrPs to specific synapses that undergo plastic adaptations is a prerequisite in synaptic consolidation. Microtubule (MT) transport critically participates in the regulation of subcellular traffic, e.g. the targeting of AMPA and NMDA receptors to dendrites and postsynaptic sites. We showed that the kinesin KIF21B regulates MT dynamics (Muhia et al., 2016, Ghiretti et al., 2016) and interacts with the trafficking factor NBEA to recycle endosomal NMDA receptors. Notably, KIF21B knockout mice exhibit deficits in social behavior, similar as NBEA KOs and autistic patients carrying NBEA polymorphisms (Gromova et al., 2018). In addition to the regulation of MT transport through motor proteins and trafficking factors, MTs are controlled by posttranslational modifications of tubulins. Here, we genetically manipulate tubulin polyglutamylation to ask whether and how altered MTs affect neuronal transport in vivo.

    STED image of hippocampal neuron
    STED image of hippocampal neuron stained with F-actin dye and bas

    P2

    Marina Mikhaylova, ZMNH Research Group Neuronal Protein Transport

    Functional Interplay of Microtubule and Actin Motors in Dendritic Compartmentalization

    One of the critical aspects in functioning and maintenance of dendrites and synapses is the well-controlled organization of cytoskeletal elements. We have shown that synaptic activation can induce dendritic stalling of secretory organelles involved in forward trafficking of membrane proteins (Mikhaylova et al., 2016). A detailed mapping of the F-actin in dendrites of primary hippocampal neurons and hippocampal slices using super-resolution microscopy indicated that there are periodic F-actin structures in the necks of nearly all dendritic spines. Our findings extend the current view on F-actin organization in dendritic spines (Bär et al., 2016, Konietzny et al., 2017). A close look at the F-actin organization and dynamics in spines revealed that the Ca2+ binding protein caldendrin plays a major role in stabilization of spinous F-actin during synaptic potentiation (Mikhaylova et al., 2018).

    Motile myosin cargo (recycling endosomes) in Purkinje cell spines
    Motile myosin cargo (recycling endosomes) in Purkinje cell spines

    P3

    Wolfgang Wagner, Institute of 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.

    Endoplasmic reticulum (yellow) visiting a dendritic spine
    Endoplasmic reticulum (yellow) visiting a dendritic spine (red)

    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

    Golgi-stained neurons of prefrontal cortex, heat maps and mEPSCs
    PFC neurons and mEPSC

    P5

    Froylan Calderon de Anda, ZMNH Research Group Neuronal Development

    TAO2 is a risk gene for neurodevelopmental disorders

    Atypical brain connectivity is a major contributor to the pathophysiology of neurodevelopmental disorders (NDDs) including Autism spectrum disorders (ASD). Thousand and one amino acid kinase 2 (TAOK2) is a family member of the mammalian sterile 20 (STE20)-like kinases and is implicated in neurodevelopmental disorders. TAOK2 is located in the ASD and schizophrenia-associated 16p11.2 chromosomal deletion region and is associated with other neurodevelopmental phenotypes. Additional evidence comes from a genome-wide association study for psychosis that identified a significant single nucleotide polymorphism in TAOK2. Finally, TAOK2 mRNA is a target of fragile X mental retardation protein (FMRP). Despite these suggestive studies, there was no direct evidence using mouse models or human cell models that genetic alterations in TAOK2 cause neurodevelopmental disorders. We performed behavioral analysis on Taok2 heterozygous (Het) and knockout (KO) mice and found gene-dosage dependent impairments in cognition, anxiety and social interaction. Taok2 Het and KO mice also have dosage-dependent abnormalities in brain size and neural connectivity in multiple regions, deficits in cortical layering, dendrite and synapse formation, and reduced excitatory neurotransmission. Whole genome and exome sequencing of ASD families identified three de novo mutations in TAOK2 and functional analysis in mice and human cells revealed that all the mutations impair protein stability, but they differentially impact kinase activity, dendrite growth, and spine/synapse development. Mechanistically, loss of Taok2 activity causes a reduction in RhoA activation, and pharmacological enhancement of RhoA activity rescues synaptic phenotypes. Together, these data provide evidence that TAOK2 is a neurodevelopmental disorder risk gene and identify RhoA signaling as a mediator of TAOK2-dependent synaptic development. (Richter M et al., 2018)

    Figure: Left panel: Golgi-stained neurons of prefrontal cortex (PFC) from postnatal day 21 WT and Taok2 KO mice. Scale bars represent 20mm. Bottom: Dendritic heat maps of superimposed neuron tracings for each condition. Blue to red (apical) and yellow to blue (basal) indicates increased probability of dendrite presence. Scale bars represent 30 mm. Right panel: Representative traces of mEPSC spikes from WT and Taok2 KO PFC neurons. Scale: 5pA vs 1sec.

    P6

    Michael Frotscher († 27.05.2017)

    Interim PI: Matthias Kneussel, ZMNH Institute of Molecular Neurogenetics

    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.

    CA1 pyramidal neuron
    CA1 pyramidal neuron

    P7

    Christine E. Gee, ZMNH Institute of Synaptic Physiology

    Simon Wiegert, ZMNH Research Group Synaptic Wiring and Information Processing

    Dynamic Rewiring of Hippocampal Circuits Following Synaptic Plasticity

    We have been investigating what determines the lifetime of synapses, the points of connections between neurons in the brain. We found that when synapses are strongly stimulated they potentiate and their lifetime is prolonged, and after depression they are more likely to disappear. When we sequentially potentiated or depressed the synapses, the last manipulation governs synaptic lifetime. We engineered new anion-conducting channelrhodopsins (eACRs), which silence neurons when light is shone on them and have developed a new technique for inducing synaptic plasticity. Using two different opsins we can independently activate neurons with 400 nm or 625 nm light. Depending on repetition frequency and the timing between spikes in the pre- and postsynaptic neurons we can cause their synapses to potentiate and see evidence of this change at least 3 days later.

    Summary Research Foci of the Research Unit FOR 2419

    Methodological Approches 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.

    More Details and References (pdf)

New FOR 2419 Projects in Second Funding Period 2019 - 2021

Project 1 Synaptic activity-dependent regulation of microtubule transport in the delivery of plasticity-related mRNAs and proteins

Matthias Kneussel ZMNH Institute of Molecular Neurogenetics

Project 2 Deciphering the functions of excitatory shaft synapses in pyramidal neurons

Marina Mikhaylova ZMNH RG Neuronal Protein Transport

Project 3 The needs of a synapse - how local microsecretory systems and organelles serve synaptic function

Michael Kreutz, ZMNH Leibniz Group Dendritic Organelles and Synaptic Function Frank F. Heisler ZMNH Institute of Molecular Neurogenetics

Project 4 Structural and functional analysis of Cav1.2 mediated PM-ER contacts in the postsynaptic membrane

Martin Heine Institute of Developmental Biology and Neurobiology of University Mainz, Kay Grünewald Heinrich-Pette-Institute Hamburg

Project 5 Synaptic plasticity: Impact on network stability and role of spine endoplasmic reticulum

Thomas Oertner and Christine Gee ZMNH Institute for Synaptic Physiology

Project 6 Synaptic plasticity and stability in the context of hippocampal information processing

J. Simon Wiegert ZMNH RG Synaptic Wiring and Information Processing

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 including proactive mentoring initiatives such as regular thesis committee meetings. By organizing seminars and symposia with internationally renowned speakers as well as training and teaching activities the students of FOR 2419 grow together as a team.

    To forster continuing education and scientific exchange the doctoral students are highly encouraged to attend the Seminars at ZMNH and those of the Hamburg Center of NeuroScience . As a teaching activity FOR 2419 students offer special methods courses to other junior scientists. For learning new research techniques, they may visit laboratories of collaboration partners and participate in international summer schools. Moreover, they join interdisciplinary research methods and academic key skill courses offered by the MIN Faculty , the Career Center of Universität Hamburg , the Hamburg Research Academy and the PIASTA Program which fosters internationalization at Universität Hamburg.

    FOR 2419 doctoral students' supervision concept is part of the ZMNH Doctoral 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 biweekly Internal PhD-Seminars for discussing own research findings.

    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.

    All advanced education and training opportunities are available for junior postdocs as well.