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Molecular mechanisms of GABAergic synapse plasticity

English title Molecular mechanisms of GABAergic synapse plasticity
Applicant Fritschy Jean-Marc
Number 132665
Funding scheme Sinergia
Research institution Institut für Pharmakologie und Toxikologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurophysiology and Brain Research
Start/End 01.11.2010 - 31.07.2014
Approved amount 1'000'000.00
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All Disciplines (4)

Discipline
Neurophysiology and Brain Research
Molecular Biology
Cellular Biology, Cytology
Biochemistry

Keywords (12)

synaptic plasticity; gephyrin; phosphorylation; mTOR; transfection; targeted gene mutation; patch clamp recording; electron microscopy; recombinant protein; synapse formation; local protein synthesis; in vivo imaging

Lay Summary (German)

Lead
Lay summary
Die Aktivität des Gehirns beruht auf einem subtilen Gleichgewicht zwischen aktivierende (glutamaterge) und hemmende (GABAerge) synaptische Einflüsse. Neuronale Schaltkreise unterliegen aber ständigen funktionellen und strukturellen Anpassungen, insbesondere durch Bildung und Abbau von neuen Synapsen. Dieser Vorgang, gekennzeichnet als "Synaptische Plastizität", spielt eine Schlüsselrolle während der Entwicklung des Gehirns und ist die Basis unserer Fähigkeit, Neues zu lernen und zu erinnern. Störungen der Synaptischen Plastizität sind folglich mit vielen neurologischen und psychiatrischen Krankheiten assoziiert.Viele Fragen sind noch offen, wie die synaptische Plastizität auf molekularer Ebene reguliert wird. Insbesondere ist wenig bekannt, wie das Gleichgewicht zwischen glutamatergen und GABAergen synaptischen Einflüsse aufrechterhalten bleibt. Das oberste Ziel dieses Projektes ist diese Frage abzuklären, durch multidisziplinäre Untersuchungen der Mechanismen der GABAergen synaptischen Plastizität, welche bisher wenig erforscht wurden. Die beteiligten Gruppen (Prof. Jean-Marc Fritschy, Universität Zürich; Prof. Dominique Muller, Universität Genf; Prof. Markus Rüegg, Universität Basel; Prof. Trevor Smart, University College London) sind international anerkannt für ihre Expertise in "Synapsen-Forschung" und verfügen um komplementäre Expertisen in Molekularbiologie, Zellbiologie, Genetik, und Elektrophysiologie. Sie werden drei Hauptprojekte verfolgen, mit den folgenden Fragenstellungen:Wie reguliert die Aktivität von neuronalen Schaltkreisen intrazelluläre Signalkaskaden, welche die Bildung oder Funktion von GABAergen Synapsen regulieren? Diese Frage wird mittels in vitro und in vivo Präparaten, zum Teil mit genetisch-veränderten Mäusen, untersucht. Insbesondere wird auch die Rolle von Hormonen (z.b. Insulin) und trophischen Faktoren auf die Plastizität von GABAergen Synapsen untersucht.Was ist die Rolle der lokalen Proteinsynthese für die Bildung und Plastizität von GABAergen Synapsen? Der Hintergrund dieser Frage ist, dass Neuronen die Fähigkeit haben, Proteine nicht zur im Zellkörper sondern auch in Dentriten zu synthetisieren, um lange Transportwege von neuen Proteinen zu vermeiden. Welcher Effekt hat eine experimentell-induzierte Störung der GABAergen synaptischen Bildung oder Funktion auf die Plastizität von glutamatergen Synapsen? Diese Frage ist für das Verständnis von neurologischen und Psychiatrischen Krankheitsbildern unerlässlich, weil es viele Hinweise dafür gibt, dass solche Störungen an die Pathogenese von Hirnkrankheiten beteiligt sind.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology.
Thomanetz Venus, Angliker Nico, Cloëtta Dimitri, Lustenberger Regula M, Schweighauser Manuel, Oliveri Filippo, Suzuki Noboru, Rüegg Markus A (2013), Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology., in The Journal of cell biology, 201(2), 293-308.
Protein kinase C regulates tonic GABA(A) receptor-mediated inhibition in the hippocampus and thalamus.
Bright Damian P, Smart Trevor G (2013), Protein kinase C regulates tonic GABA(A) receptor-mediated inhibition in the hippocampus and thalamus., in The European journal of neuroscience, 38(10), 3408-23.
Excitatory synaptic activity is associated with a rapid structural plasticity of inhibitory synapses on hippocampal CA1 pyramidal cells
Lushnikova I, Skibo G, Muller D, Nikonenko I. (2011), Excitatory synaptic activity is associated with a rapid structural plasticity of inhibitory synapses on hippocampal CA1 pyramidal cells, in Neuropharmacology, 60, 757-764.
Regulation of GABAergic synapse formation and plasticity by GSK3beta-dependent phosphorylation of gephyrin
Tyagarajan SK, Ghosh H, Yévenes GE, Nikonenko I, Ebeling C, Schwerdel C, Sidler C, Zeilhofer HU, Gerrits B, Muller D, Fritschy JM. (2010), Regulation of GABAergic synapse formation and plasticity by GSK3beta-dependent phosphorylation of gephyrin, in Proceedings of the National Academy of Sciences, USA, 108, 379-384.
Modulation of neurosteroid potentiation by protein kinases at synaptic- and extrasynaptic-type GABAA receptors
Adams J.M. Thomas P. & Smart T.G., Modulation of neurosteroid potentiation by protein kinases at synaptic- and extrasynaptic-type GABAA receptors, in Neuropharmacology.

Collaboration

Group / person Country
Types of collaboration
McGill University Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
2012 Society for Neuroscience annual meeting Poster Proteins involved in the SUMO pathway modulate gephyrin scaffolding and GABAergic transmission 17.10.2012 New Orleans, United States of America Fritschy Jean-Marc;


Self-organised

Title Date Place
Mechanisms of GABAergic synaptic plasticity 27.02.2013 Chexbres, Switzerland

Awards

Title Year
Gaddum Memorial Medal. Dec 2012. Awarded biennially by the British Pharmacological Society 2012

Associated projects

Number Title Start Funding scheme
133133 Molecular mechanisms involved in the formation and modulation of synapses 01.10.2010 Project funding
127552 Molecular control of spine dynamics in hippocampal slice cultures 01.10.2009 Project funding
144199 Do limbic seizures contribute to Alzheimer's disease-like pathology? Relevance of immune-mediated mechanisms 01.10.2012 Project funding
149783 Molecular mechanisms of synaptic plasticity and skeletal muscle homeostasis 01.10.2013 Project funding
130495 Regulation of GABAergic synapse formation and plasticity by posttranslational control of gephyrin 01.04.2010 Project funding
118388 Molecular mechanisms involved in the formation and modulation of synapses 01.10.2007 Project funding
146120 Signaling complexes associated with GABAergic synapses and their relevance for the regulation of adult neurogenesis 01.06.2013 Project funding

Abstract

Synaptic homeostasis is a critically important aspect of nervous system function, endowing the brain with life-long plasticity. It maintains a balance between excitatory and inhibitory neurotransmission whilst allowing local changes in synaptic strength and connectivity that form the basis of learning and memory. Adjustments to the excitability of individual neurons, and the consequences this will have for the level of activity in neural networks, involve postsynaptic adaptations in signal processing and transduction. Given its importance, perturbations of synaptic homeostasis might therefore be expected to cause profound alterations to brain function and indeed, major neurological and psychiatric diseases are linked to such dysfunctions. Mechanistically, changes in excitability involving glutamatergic synapses ought to be paralleled by corresponding changes at GABAergic synapses to avoid hyperexcitation (or silencing) of the network. However, the molecular mechanisms underlying this coordinated control are largely unknown, mainly because plasticity of GABAergic synapses is poorly understood. The aim of this collaborative research project is to investigate molecular mechanisms regulating GABAergic synaptic plasticity and to understand how these synapses respond to changes in neuronal activity in the context of homeostatic plasticity. A major tenet of our proposal is that synaptic homeostasis depends on signaling cascades regulating in parallel the efficacy of glutamatergic and GABAergic transmission. We surmise that these signals converge onto postsynaptic protein scaffolds to regulate synaptic function by means of posttranslational modifications of specific target proteins and control of local protein synthesis. Such convergence is apparent in the concerted changes in synaptic function produced by specific protein kinases and phosphatases, as well as in the regulation of signaling complexes regulating mRNA translation at synaptic sites, notably the mammalian target of rapamycin (mTOR) complexes. We will therefore focus on the integration of these signaling mechanisms by gephyrin, the major postsynaptic scaffold protein in GABAergic synapses, to determine their contribution to the regulation of GABAergic neurotransmission. We plan three multidisciplinary research projects to investigate: 1) The dynamic regulation of GABAA receptor-gephyrin complexes by protein phosphorylation, and its cross-talk with glutamatergic synapses, with a focus on Ca++-calmodulin-dependent kinase 2 and protein phosphatase 1; 2) the role of mTORC1 and mTORC2 signaling complexes in regulating GABAergic synapses in developing and mature neuronal circuits, as well as the significance of mTOR-gephyrin interaction for local regulation of signal transduction in inhibitory synapses; 3) the relevance of gephyrin regulation by activity-dependent phosphorylation mechanisms, as well as by mTOR-mediated signaling, for adjusting GABAergic synapse function following global perturbation of network activity. These three projects are designed to cross-fertilize by integrating findings from different levels of analysis using a common set of tools (expression plasmids, mutant mice) and experimental paradigms in vitro and in vivo. For successful completion, each project requires the joint contribution of several teams in our consortium (Jean-Marc Fritschy, project coordinator, University of Zurich; Dominique Muller, University of Geneva; Markus A. Rüegg, University of Basel; Trevor G. Smart, University College London).The four co-applicants are all internationally recognized experts in the field. The synergy will arise from our complementary expertise in molecular and cellular neurobiology, electrophysiology, live-cell imaging, morphology, and electron microscopy, which we will use to address our aims from a strong multidisciplinary perspective. The results will contribute to characterize molecular mechanisms of GABAergic synaptic plasticity and its role in synaptic homeostasis and excitatory - inhibitory balance. By fundamentally understanding how changes in network activity affect neuronal processing and synaptic function, these studies will provide insight into not just mechanisms of brain plasticity but also the pathophysiology of debilitating brain diseases.
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