Research Unit FOR 2419 funded by the DFG
Plasticity versus Stability - Molecular Mechanisms of Synaptic Strength
Coordinator: Prof. Dr. Matthias Kneussel
Contact: 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 seven projects, FOR 2419 scientists investigate different aspects of activity-dependent structural and functional synaptic plasticity at the molecular and cellular level.
FOR 2419-Seminars and Research Highlights
Upcoming and past FOR 2419 Seminars and Conferences
September 20, 2018 at 2 pm
Prof. Ryuichi Shigemoto, MD , PhD, Institute of Science and Technology Austria, Klosterneuburg
Host: Dr. Wolfgang Wagner
Venue: Center for Molecular Neurobiology Hamburg (ZMNH), seminar room E.82
November 15, 2018 at 2 pm
Prof. Dr. Karen Zito , University of California/Davis, Center for Neuroscience
Host: Dr. Christine Gee
Venue: Center for Molecular Neurobiology (ZMNH), seminar room E.82
Past FOR 2419-Seminars and Conferences
"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)
Research Highlights of the FOR 2419 project groups
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.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. During the first funding period 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.
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
The Role of TAO2 in Synapse Formation and Plasticity
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.
Figure legend: Left panel: Golgi-stained PFC neurons 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 30mm. Right panel: Representative traces of mEPSC spikes from WT and Taok2 KO PFC neurons. Scale: 5pA vs 1sec.
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.
Publications of FOR 2419
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
Helassa N, Dürst CD, Coates C, Arif U, Schulze C, Wiegert JS, Geeves M, Oertner TG, Török K (2018) Ultrafast glutamate sensors resolve short-term synaptic plasticity. Proc Natl Acad Sci USA early online
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
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
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. 2018 Mar 8. doi: 10.1007/s00018-018-2791-2. [Epub ahead of print] PubMed
Wiegert JS, Pulin M, Gee CE, Oertner TG (2018) The fate of hippocampal synapses depends on the sequence of plasticity-inducing events. bioRxiv
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
Scharkowski F, Frotscher M, Lutz D, Korte M, Michaelsen-Preusse K (2017) Altered connectivity and synapse maturation of the hippocampal mossy fiber pathway in a mouse model of the fragile X syndrome. Cereb Cortex doi: 10.1093/cercor/bhw408. [Epub ahead of print] 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
Kneussel, M (2016) DFG Forschergruppe FOR 2419 „Plastizität versus Stabilität: Molekulare Mechanismen der Synapsenstärke“. Neuroforum 22, 60-61.
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 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 biweekly 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.
All advanced education and training opportunities are available for junior postdocs as well.