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: Dr. Eva-Maria Suciu
Tel.: +49 (0) 40 7410 - 55028, firstname.lastname@example.org
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 2419 Events and Research Highlights
FOR 2419 Seminars and Conferences
September 26, 2019 at 2 pm
Dr. Marie-Jo Moutin , Grenoble Institute of Neurosciences
Host: Dr. Marina Mikhaylova
Venue: Center for Molecular Neurobiology Hamburg (ZMNH), seminar room E.82
October 1, 2019 at 2 pm
Dr. Johannes Letzku, MPI for Brain Research Frankfurt/Main
Host: Prof. Simon Wiegert
Venue: Center for Molecular Neurobiology Hamburg (ZMNH), seminar room E.82
November 18, 2019 at 2 pm
Prof. Antonia Roll-Mecak , NIH, Bethesda, MD
Host: Prof. Matthias Kneussel
Venue: Center for Molecular Neurobiology Hamburg (ZMNH), seminar room E.82
International FOR 2419 - Symposium on June 3 - 5, 2020
Past FOR 2419 - Seminars and Conferences
Dr. Tomomi Shimogori , RIKEN Center for Brain Science, Japan Activity dependent Btbd3 protein dynamics for selective dendrite morphogenesis in developing neuron
"Uncovering Synaptic Plasticity: From Molecules to Memory" International FOR 2419 Symposium 2018: Scientific Program (pdf 301 KB)
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 of FOR 2419
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
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
Calderon de Anda F, Gaertner A (2018) Editorial: Neuronal Polarity: Establishment and Maintenance. Front Cell Neurosci 12:137. 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
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 (2018) Radial F-actin organization during early neuronal development. BioRxiv doi: https://doi.org/10.1101/372813
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 e1114. *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?
Oda K, Vierock J, Oishi S, Rodriguez-Rozada S, Taniguchi R, Yamashita K, Wiegert JS, Nishizawa T, Hegemann P, Nureki O (2018) Crystal structure of the red light-activated channelrhodopsin Chrimson. Nat Commun 9:3949. 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 (2018) Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling. Mol Psychiatry. 2018 Feb 21. doi: 10.1038/s41380-018-0025-5. [Epub ahead of print] PubMed
Scharkowski F, Frotscher M, Lutz D, Korte M, Michaelsen-Preusse K (2018) Altered connectivity and synapse maturation of the hippocampal mossy fiber pathway in a mouse model of the fragile X syndrome. Cereb Cortex 28:852-886. 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
Schiewek J, Schumacher U, Lange T, Wikman H, Pantel K, Mikhaylova M, Kneussel M, Linder S, Schmalfeldt B, Oliveira-Ferrer L, Windhorst S (2018) Clinical relevance of cytoskeleton associated proteins for ovarian cancer. J Cancer Res Clin Oncol 2018 Aug 9. doi: 10.1007/s00432-018-2710-9. [Epub ahead of print] 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. 2018 Mar 8. doi: 10.1007/s00018-018-2791-2. [Epub ahead of print] 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
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 2018 Sep 10. https://doi.org/10.1038/s41564-018-0236-1 [Epub ahead of print] 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, 2018 Aug 6. doi: 10.1002/humu.23602. [Epub ahead of print] PubMed
Wang S, Brunne B, Zhao S, Chai X, Li J, Lau J, Failla AV, Zobiak B, Sibbe M, Westbrook GL, Lutz D, Frotscher M (2018) Trajectory analysis unveils Reelin's role in the directed migration of granule cells in the dentate gyrus. J Neurosci 38:137-148. 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
Wietek, J., Rodriguez-Rozada, S., Tutas, J., Tenedini, F., Grimm, C., Oertner, T. G., Soba, P., Hegemann, P. & Wiegert, J. S (2018) Author Correction: Anion-conducting channelrhodopsins with tuned spectra and modified kinetics engineered for optogenetic manipulation of behavior. Sci Rep 8;4765 PubMed
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
Frese CK*, Mikhaylova M*, Stucchi R*, Gautier V, Liu Q, Mohammed S, Heck AJR, Altelaar AFM, Hoogenraad CC (2017) Quantitative map of proteome dynamics during neuronal differentiation. Cell Reports 18:1527-42.* shared first authorship PubMed
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
Katrukha EA*, Mikhaylova M*, van Brakel HX, van Bergen En Henegouwen PM, Akhmanova A, Hoogenraad CC, Kapitein LC (2017) Probing cytoskeletal modulation of passive and active intracellular dynamics using nanobody-functionalized quantum dots. Nat Commun 8:14772.
* shared first authorship 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
Vogl C, Butola T, Haag N, Hausrat T, Leitner M, Moutschen M, Lefebvre P, Speckmann C, Garrett L, Becker L, Fuchs H, Hrabe de Angelis M, Nietzsche S, Oliver D, Kessels M, Kneussel M, Kilimann M, Strenzke N (2017) The BEACH protein LRBA is required for hair bundle maintenance in cochlear hair cells and for hearing. EMBO Rep 18:2015-2029. 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
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
Cheng J*, Sahani S*, Hausrat TJ*, Yang JW, Ji H, Schmarowski N, Endle H, Liu X, Li Y, Bottche R, Radyushkin K, Maric HM, Hoerder-Suabedissen A, Molnar Z, Prouvot PH, Trimbuch T, Ninnemann O, Huai J, Fan W, Visentin B, Sabbadini R, Stromgaard K, Stroh A, Luhmann HJ, Kneussel M, Nitsch R, Vogt J (2016) Precise somatotopic thalamocortical axon guidance depends on LPA-mediated PRG-2/Radixin signaling. Neuron 92:126-142. *Co-first authors PubMed
Gee CE, Oertner TG (2016) Neurobiology: Pull out the stops for plasticity. Nature 529:164-165. PubMed
Ghiretti AE, Thies E, Tokito MK, Lin T, Ostap EM, Kneussel M, Holzbaur EL (2016) Activity-Dependent Regulation of Distinct Transport and Cytoskeletal Remodeling Functions of the Dendritic Kinesin KIF21B. Neuron 92:857-872. 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
Mikhaylova M, Bera S, Kobler O, Frischknecht R, Kreutz MR (2016) A dendritic Golgi satellite between ERGIC and retromer. Cell Rep 14:189-199. 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
Wiegert JS, Oertner TG (2016) How (not) to silence long-range projections with light. Nat Neurosci 19:527-528. PubMed
Press releases and Previews in Scientific Journals
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 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
Resonance in international press
April 4, 2018
Preview of Mikhaylova et al. (2018) Neuron 97:1110-1125 e11
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.
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
Research Highlights of the FOR 2419 in the First Funding Period 2016 - 2018NBEA and KIF21B regulate synaptic NMDA receptor recycling
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 stained with F-actin dye and bas
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
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 (red)
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 spinePFC neurons and mEPSC
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.
Michael Frotscher († 27.05.2017)
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
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 2419Methodological 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.
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
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
Early career support
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 theSeminars 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.
Publications, talks and posters presented by FOR 2419 doctoral students
as on April 25, 2019 (pdf)