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Signaling complexes associated with GABAergic synapses and their relevance for the regulation of adult neurogenesis

English title Signaling complexes associated with GABAergic synapses and their relevance for the regulation of adult neurogenesis
Applicant Fritschy Jean-Marc
Number 146120
Funding scheme Project funding
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 01.06.2013 - 31.05.2016
Approved amount 525'000.00
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All Disciplines (4)

Discipline
Neurophysiology and Brain Research
Molecular Biology
Cellular Biology, Cytology
Pharmacology, Pharmacy

Keywords (10)

neuroligin2; gephyrin; GABAA receptor; adult neurogenesis; postsynaptic density; dystrophin-associated glycoprotein complex; neuronal nitric oxide synthase; immuno-electron microscopy; Lentiviral vectors; CREB

Lay Summary (German)

Lead
Botenstoffe spielen eine zentrale Rolle für die synaptische Übertragung im ZNS. Sie steuern zahlreiche weitere Mechanismen, wie die Entstehung und Reifung von neugeborenen Neuronen. Deshalb können Störungen der Funktion von Neurotransmittern die Bildung und Plastizität des Gehirns beeinträchtigen, wie es bei vielen neurologischen und psychiatrischen Krankheiten der Fall ist. Dieses Gesuch fokussiert auf diese Fragen für den Botenstoff GABA, dem Haupt hemmenden Neurotransmitter im ZNS.
Lay summary

Die GABAerge Neurotransmission ist an die Entwicklung des ZNS beteiligt; sie steuert sowohl die Proliferation von Stammzellen wie auch die funktionelle Differenzierung von Neuronen. Folglich liegt nahe, dass Störungen der GABAergen Übertragung, oder Störungen der Regulation von GABAergen Synapsen durch intrazelluläre Signalkaskaden, kausal mit der Entstehung von psychiatrischen und Entwicklungsbedingten Hirnkrankheiten verbunden sind könnte.

Dieses Gesuch hat für Ziel zu untersuchen, wie die GABAerge Neurotransmission und intrazelluläre Signalkaskaden miteinander gekoppelt sind, um die Reifung und Funktion von Neuronen zu steuern. Dabei werden wir folgende Untersuchungen führen:

1) Aufschlüsselung der molekularen Zusammensetzung und der Funktion von Signalkomplexen an GABAergen Synapsen. Spezifisch werden wir untersuchen wie der Dystrophin-Glykoprotein-Komplex mit Komponenten von GABAergen Synapsen assoziiert ist, und dessen Funktionen reguliert. Ähnlicherweise werden wir untersuchen, wie nNOS an GABAergen Synapsen verankert und reguliert wird.

2) Rolle von Stickstoffmonoxid für die Regulation von GABAergen Synapsen und die Reifung von neugeborenen Neuronen im adulten Gehirn. Dieses Projekt wird etablieren, wie nNOS die Differenzierung, synaptische Integration und Plastizität von neugeborenen Neuronen im adulten Gehirn steuert.

3) Rolle der GABAergen Neurotransmission für die Regulation der CREB Aktivität in neugeborenen Neuronen.

Jedes von diesen drei Projekten ist von Bedeutung für das Verständnis der Beteiligung der GABAergen Neurotransmission an die Pathophysiologie von Hirnkrankheiten. Im Projekt 1 setzt sich der Fokus auf die Mentalretardierung bei Patienten mit Duchenne-Muskeldystrophie und Autismus. Die Relevanz von Projekt 2 ist für unser Verständnis der Neurogenese sehr hoch. Schliesslich wird Projekt 3 potentiell grosse Auswirkungen auf unser Verständnis von Lernen und Gedächtnis haben. 

Direct link to Lay Summary Last update: 07.04.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Interneuron- and GABA(A) receptor-specific inhibitory synaptic plasticity in cerebellar Purkinje cells.
He Qionger, Duguid Ian, Clark Beverley, Panzanelli Patrizia, Patel Bijal, Thomas Philip, Fritschy Jean-Marc, Smart Trevor G (2015), Interneuron- and GABA(A) receptor-specific inhibitory synaptic plasticity in cerebellar Purkinje cells., in Nature communications, 6, 7364-7364.
Postsynaptic gephyrin clustering controls the development of adult-born granule cells in the olfactory bulb.
Deprez Francine, Pallotto Marta, Vogt Fabia, Grabiec Marta, Virtanen Mari A, Tyagarajan Shiva K, Panzanelli Patrizia, Fritschy Jean-Marc (2015), Postsynaptic gephyrin clustering controls the development of adult-born granule cells in the olfactory bulb., in The Journal of comparative neurology, 523(13), 1998-2016.
Significance of GABA(A) receptor heterogeneity: clues from developing neurons.
Fritschy Jean-Marc (2015), Significance of GABA(A) receptor heterogeneity: clues from developing neurons., in Advances in pharmacology (San Diego, Calif.), 73, 13-39.
A protocol for concurrent high-quality immunohistochemical and biochemical analyses in adult mouse central nervous system.
Notter Tina, Panzanelli Patrizia, Pfister Sandra, Mircsof Dennis, Fritschy Jean-Marc (2014), A protocol for concurrent high-quality immunohistochemical and biochemical analyses in adult mouse central nervous system., in The European journal of neuroscience, 39(2), 165-75.
GABAA receptors and plasticity of inhibitory neurotransmission in the central nervous system.
Fritschy Jean-Marc, Panzanelli Patrizia (2014), GABAA receptors and plasticity of inhibitory neurotransmission in the central nervous system., in The European journal of neuroscience, 39(11), 1845-65.
Gephyrin: a master regulator of neuronal function?
Tyagarajan Shiva K, Fritschy Jean-Marc (2014), Gephyrin: a master regulator of neuronal function?, in Nature reviews. Neuroscience, 15(3), 141-56.
Mitochondrial reactive oxygen species regulate the strength of inhibitory GABA-mediated synaptic transmission.
Accardi Michael V, Daniels Bryan A, Brown Patricia M G E, Fritschy Jean-Marc, Tyagarajan Shiva K, Bowie Derek (2014), Mitochondrial reactive oxygen species regulate the strength of inhibitory GABA-mediated synaptic transmission., in Nature communications, 5, 3168-3168.
Pin1-dependent signalling negatively affects GABAergic transmission by modulating neuroligin2/gephyrin interaction.
Antonelli Roberta, Pizzarelli Rocco, Pedroni Andrea, Fritschy Jean-Marc, Del Sal Giannino, Cherubini Enrico, Zacchi Paola (2014), Pin1-dependent signalling negatively affects GABAergic transmission by modulating neuroligin2/gephyrin interaction., in Nature communications, 5, 5066-5066.
Partial inactivation of GABAA receptors containing the α5 subunit affects the development of adult-born dentate gyrus granule cells.
Deprez Francine, Vogt Fabia, Floriou-Servou Amalia, Lafourcade Carlos, Rudolph Uwe, Tyagarajan Shiva K, Fritschy Jean-Marc, Partial inactivation of GABAA receptors containing the α5 subunit affects the development of adult-born dentate gyrus granule cells., in The European journal of neuroscience.

Collaboration

Group / person Country
Types of collaboration
Dr. Patrizia Panzanelli Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. Pierre-Marie Lledo France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Uwe Rudolph United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Peter Scheiffele Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events



Self-organised

Title Date Place
2015 GRC Inhibition in the CNS 16.08.2015 Lewinston, Maine, United States of America

Associated projects

Number Title Start Funding scheme
166130 GABAA receptor heterogeneity in striatal neurons: significance for Parkinson's disease 01.06.2016 Project funding
144199 Do limbic seizures contribute to Alzheimer's disease-like pathology? Relevance of immune-mediated mechanisms 01.10.2012 Project funding
150770 High-resolution rodent ultrasound system for guided in utero injection and electroporation 01.12.2013 R'EQUIP
130495 Regulation of GABAergic synapse formation and plasticity by posttranslational control of gephyrin 01.04.2010 Project funding
132665 Molecular mechanisms of GABAergic synapse plasticity 01.11.2010 Sinergia

Abstract

In recent years, major advances have been made in our understanding of GABAergic neurotransmission, and its contribution to brain development, synaptic plasticity, and pathophysiology of neurological and neuropsychiatric disorders. First, GABAergic interneurons were shown to be highly specialized and modulate the activity of principal cells in a behaviorally-relevant manner. Second, GABAergic transmission is fine-tuned by a vast array of signaling cascades controlling the structure and function of GABAergic synapses to optimize the function of brain circuits. Third, there is extensive evidence demonstrating that GABAergic transmission, mediated by synaptic and extrasynaptic receptors, controls every step of neuronal development, from precursor cell proliferation to synaptic integration of differentiating neurons, both during ontogeny and in adult neurogenesis. Therefore, perturbations of GABAergic signaling, or alterations of signaling cascades regulating GABAergic synapses, are likely to be causally related to the pathophysiology of psychiatric and neurodevelopmental brain diseases, due to abnormal circuit formation or functional dysregulation.This grant proposal goes one step further and aims to investigate how GABAergic transmission cooperates with intracellular signaling pathways to modulate neuronal function and differentiation. Based on our recent work in vitro on the regulation of gephyrin, the main scaffolding molecule of GABAergic synapses, and on our in vivo studies of the molecular make-up of GABAergic synapses, we speculate that postsynaptic gephyrin scaffolds are associated in a synapse-specific manner with two major signaling complexes, the dystrophin-glycoprotein complex (DGC) and neuronal nitric oxide synthase (nNOS) and its regulatory proteins, thereby representing a hub for signaling pathways to regulate neuronal development and synaptic plasticity. Further, we have obtained preliminary evidence indicating that a specific GABAA receptor subtype, containing the alpha5 subunit, mediates activation of the transcription factor CREB in adult-born neurons. We will use here a multidisciplinary approach, combining molecular and cellular biology, biochemistry, immunohistochemistry, and electrophysiology to address the following issues: 1) Molecular composition and function of signaling complexes present at GABAergic synapsesIn this project, we will investigate how the DGC is associated with specific constituents of GABAergic synapses, notably through interactions with neuroligin2, and how signaling molecules bound to the DGC regulate GABAergic synapse formation and plasticity. In a second set of experiments, we will assess how nNOS is anchored at GABAergic synapses. In particular, we will test the hypothesis that gephyrin modulates nNOS localization and activity at GABAergic synapses, by forming a ternary complex with GRIP1 and/or Dlc1/PIN, two proteins known to interact with gephyrin and with nNOS. 2) Role of nNOS-mediated regulation of GABAergic function for adult-born neuron differentiationThis project will unravel how nNOS, a negative regulator of adult neurogenesis, is involved in differentiation, synaptic integration, and functional plasticity of adult-born neurons, and whether these functions depend on its anchoring at GABAergic synapses, thereby highlighting the importance of gephyrin clustering for regulation of adult neurogenesis by nNOS.3) Role of alpha5-GABAA receptors in the control of CREB-mediated regulation of adult neurogenesisThis project will address the link between GABAergic transmission and the regulation of CREB activity in adult-born neurons. Based on our preliminary evidence pointing to a key role GABAA receptors containing the alpha5 subunit in neuronal fate decision and early maturation of neural progenitor cells of the dentate gyrus, we will investigate here using conditional gene deletion in vivo the signaling cascades depending of ?5-GABAA receptors and their role in newborn dentate gyrus granule cells.Each of these projects is of immediate relevance for understanding the role of GABAergic transmission in the pathophysiology of brain diseases. In project 1, the focus on the DGC and neuroligin2 is directly related to mental retardation and cognitive impairments affecting patients with Duchenne muscle dystrophy and with autism-related disorders. In project 2, the role of nNOS for neuronal development and differentiation is relevant in the context of cell-replacement therapies based on neurogenesis. Finally, project 3, expected to link GABAergic transmission to activation of CREB signaling, will have a major impact on our understanding of hippocampal function for learning and memory.
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