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Molecular control of spine dynamics in hippocampal slice cultures

English title Molecular control of spine dynamics in hippocampal slice cultures
Applicant Muller Dominique
Number 127552
Funding scheme Project funding (Div. I-III)
Research institution Dépt des Neurosciences Fondamentales Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.10.2009 - 30.09.2012
Approved amount 755'000.00
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Keywords (8)

Synaptic plasticity; synaptogenesis; development; mental retardation; hippocampus; plasticity; brain networks; learning and memory

Lay Summary (English)

Lead
Lay summary
LeadRemodeling of excitatory synapses on dendritic spines is a continuous process that shapes the organization of synaptic networks with experience. Alterations of these processes have been proposed to underlie several forms of developmental neuropsychiatric disorders. This project aims at investigating the molecular mechanisms controlling this plasticity.RésuméThis project proposes to use repetitive confocal imaging of hippocampal slice cultures together with genetic and molecular manipulations of synaptic proteins and 3D electron microscopic reconstruction of identified spines to assess spine properties and dynamics during development. With this approach we will aim at three main objectives. i) we will investigate mechanisms regulating spine formation and synapse number and specifically test the role of signaling pathways such as Rho GTPases in controlling growth of new protrusions in response to activity change. ii) We will determine the role of N-cadherin in promoting activity-mediated spine stability and persistence. iii) We will test the hypothesis that expression of mutants of the mental retardation genes PAK3 and FMR1 are associated with disruption of spine dynamics.ButThe central aim of this project is to uncover regulatory mechanisms that control the development and specificity of cortical synaptic networks. The hypothesis is that altered spine dynamics may result in defects in the specificity of synaptic networks and thereby account for the cognitive dysfunctions associated with specific forms of mental diseases. SignificationSpine dynamics critically determine the rules of network organization and selectivity during development. Understanding the molecular mechanisms controlling these properties of plasticity is expected to provide important insight about the pathogenetic mechanisms underlying specific forms of mental retardation. Additionally, by examining specific molecular hypotheses about the control of synapse number and stability and then determining how these mechanisms might contribute to two forms of mental retardation, these experiments could lead to new development addressing possible therapeutic approaches of these diseases.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Name Institute

Employees

Publications

Publication
Deletion of glutamate dehydrogenase 1 (Glud1) in the central nervous system affects glutamate handling without altering synaptic transmission.
Frigerio Francesca, Karaca Melis, De Roo Mathias, Mlynárik Vladimír, Skytt Dorte M, Carobbio Stefania, Pajęcka Kamilla, Waagepetersen Helle S, Gruetter Rolf, Muller Dominique, Maechler Pierre (2012), Deletion of glutamate dehydrogenase 1 (Glud1) in the central nervous system affects glutamate handling without altering synaptic transmission., in Journal of neurochemistry, 123(3), 342-8.
Structural plasticity upon learning: regulation and functions
Caroni P., Donato F., Muller D. (2012), Structural plasticity upon learning: regulation and functions, in Nat. Rev. Neurosci, 13, 478-490.
Influence of matrix metalloproteinase MMP-9 on dendritic spine morphology.
Michaluk Piotr, Wawrzyniak Marcin, Alot Przemyslaw, Szczot Marcin, Wyrembek Paulina, Mercik Katarzyna, Medvedev Nikolay, Wilczek Ewa, De Roo Mathias, Zuschratter Werner, Muller Dominique, Wilczynski Grzegorz M, Mozrzymas Jerzy W, Stewart Michael G, Kaczmarek Leszek, Wlodarczyk Jakub (2011), Influence of matrix metalloproteinase MMP-9 on dendritic spine morphology., in Journal of cell science, 124(Pt 19), 3369-80.
Developmental Stage-dependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex.
Briner Adrian, Nikonenko Irina, De Roo Mathias, Dayer Alexandre, Muller Dominique, Vutskits Laszlo (2011), Developmental Stage-dependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex., in Anesthesiology, 115(2), 282-93.
Excitatory synaptic activity is associated with a rapid structural plasticity of inhibitory synapses on hippocampal CA1 pyramidal cells.
Lushnikova Irina, Skibo Galina, Muller Dominique, Nikonenko Irina (2011), Excitatory synaptic activity is associated with a rapid structural plasticity of inhibitory synapses on hippocampal CA1 pyramidal cells., in Neuropharmacology, 60(5), 757-64.
Regulation of GABAergic synapse formation and plasticity by GSK3beta-dependent phosphorylation of gephyrin.
Tyagarajan Shiva K, Ghosh Himanish, Yévenes Gonzalo E, Nikonenko Irina, Ebeling Claire, Schwerdel Cornelia, Sidler Corinne, Zeilhofer Hanns Ulrich, Gerrits Bertran, Muller Dominique, Fritschy Jean-Marc (2011), Regulation of GABAergic synapse formation and plasticity by GSK3beta-dependent phosphorylation of gephyrin., in Proceedings of the National Academy of Sciences of the United States of America, 108(1), 379-84.
Role of NCAM in spine dynamics and synaptogenesis.
Muller D, Mendez P, De Roo M, Klauser P, Steen S, Poglia L (2010), Role of NCAM in spine dynamics and synaptogenesis., in Advances in experimental medicine and biology, 663, 245-56.
Signaling mechanisms regulating synapse formation and function in mental retardation.
Boda Bernadett, Dubos Aline, Muller Dominique (2010), Signaling mechanisms regulating synapse formation and function in mental retardation., in Current opinion in neurobiology, 20(4), 519-27.
Bilateral whisker trimming during early postnatal life impairs dendritic spine development in the mouse somatosensory barrel cortex.
Briner Adrian, De Roo Mathias, Dayer Alexandre, Muller Dominique, Kiss Jozsef Z, Vutskits Laszlo (2010), Bilateral whisker trimming during early postnatal life impairs dendritic spine development in the mouse somatosensory barrel cortex., in The Journal of comparative neurology, 518(10), 1711-23.
N-cadherin mediates plasticity-induced long-term spine stabilization.
Mendez Pablo, De Roo Mathias, Poglia Lorenzo, Klauser Paul, Muller Dominique (2010), N-cadherin mediates plasticity-induced long-term spine stabilization., in The Journal of cell biology, 189(3), 589-600.
Volatile anesthetics rapidly increase dendritic spine density in the rat medial prefrontal cortex during synaptogenesis.
Briner Adrian, De Roo Mathias, Dayer Alexandre, Muller Dominique, Habre Walid, Vutskits Laszlo (2010), Volatile anesthetics rapidly increase dendritic spine density in the rat medial prefrontal cortex during synaptogenesis., in Anesthesiology, 112(3), 546-56.
Alteration of synaptic network dynamics by the intellectual disability protein PAK3
Dubos Aline, Alteration of synaptic network dynamics by the intellectual disability protein PAK3, in J. Neurosci.
Estradiol promotes spine growth and synapse formation without affecting pre-established networks.
Mendez Pablo, Garcia-Segura Luis Miguel, Muller Dominique, Estradiol promotes spine growth and synapse formation without affecting pre-established networks., in Hippocampus.
Ultrastructural modifications of spine and synapse morphology by SAP97.
Poglia Lorenzo, Muller Dominique, Nikonenko Irina, Ultrastructural modifications of spine and synapse morphology by SAP97., in Hippocampus.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Synaptic Bases of Disease 11.07.2012 Geneva, Switzerland
European Synapse Meeting 12.10.2011 Balatonfüred
ISN meeting 28.08.2011 Athens
IBRO meeting 14.07.2011 Florence
Spring hippocampal meeting 22.05.2011 Verona
SSN annual meeting 26.03.2011 Basel
CNRS Monod conference on Mental retardation 07.10.2010 Roscoff


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Jussieu seminar 17.06.2011 Paris
Navarra University seminar 08.04.2011 Pamplona
IGBCM seminar 29.03.2011 Strassbourg


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions semaine sur le cerveau Western Switzerland

Associated projects

Number Title Start Funding scheme
132665 Molecular mechanisms of GABAergic synapse plasticity 01.11.2010 Sinergia
144080 Molecular control of spine dynamics in hippocampal organotypic cultures 01.10.2012 Project funding (Div. I-III)
105721 Molecular mechanisms contributing to synaptogenesis in hippocampal slice cultures 01.10.2004 Project funding (Div. I-III)

Abstract

Formation, elimination and remodeling of excitatory synapses on dendritic spines is a continuous process that shapes the organization of synaptic networks during development, but also contributes to adapt cir-cuits to experience in more mature tissue. The mechanisms underlying this structural synapse dynamics therefore critically determine the rules of network selectivity and organization and alterations of these processes have been proposed to underlie several forms of developmental neuropsychiatric disorders, including mental retardation, autism or schizophrenia. Very little is known about the molecular mechanisms that control this structural plasticity. We propose here to address this issue using hippocampal slice cultures and technological advances that allow to com-bine genetic and molecular manipulations of synaptic proteins together with repetitive confocal imaging of spine morphology, functional analyses of synaptic activity and 3D electron microscopic reconstruction of identified spines. With this approach, our aim is to identify molecular mechanisms underlying spine formation and stabilization and test the hypothesis that defects in the dynamics of synapse formation and stabilization are associated with specific forms of mental retardation.The specific objectives will be: i)to identify mechanisms regulating spine formation and synapse number. Based on preliminary evi-dence, we hypothesize that synapse number could be regulated by two different mechanisms: a homeo-static process that is determined by the balance between excitation/inhibition; and a process linked to plasticity and regulated in a more local manner. Using excitatory and inhibitory receptor agonists or an-tagonists and conditions that induce plasticity, we propose to investigate this hypothesis and compare mechanisms of spine growth under these conditions. Specifically we will examine the rate of formation and distribution of newly formed spines, the requirement for protein synthesis, the role of growth fac-tors, calcium signaling, Rho GTPases and activity. ii) to identify the molecular mechanisms regulating spine stability and persistence. We recently showed that synaptic plasticity, LTP and rhythmic theta activity promote a long-term stabilization of activated synapses, a process that is crucial for a selective development of synaptic networks. We hypothesize that this stabilization effect could be linked to the expression of specific molecules, namely adhesion molecules and propose to test the role of N-cadherin. For this we will use loss and gain of function ex-periments using mutant cadherins to test spine stability, LTP-induced spine stabilization, we will ana-lyze cadherin expression as a function of specific patterns of activity, examine how N-cadherin affects the ultrastructure of the synapse and investigate the possible link between cadherin, scaffolding pro-teins such as PSD95 and Rho GTPases and PAK signaling.iii) to investigate whether defects in spine dynamics underlie the defects in spine morphogenesis associ-ated with expression of mutant PAK3 gene (a downstream effectors of Rho GTPases) or suppression of the fragile X protein in FMR1 KO mice. As an additional model, we also plan to generate an induc-ible mouse model of the MRX30 human mutation. In these models we will test whether altered spine turnover, defects in protrusion growth, in spine maturation or in activity-dependent stabilization could be involved. A second objective, if alterations are found, will be to test the possibility to reverse the defects by selectively targeting previously identified modulators of spine dynamics such as receptors (namely metabotropic receptors), the growth factor BDNF, N-cadherin or molecules regulating the Rho GTPase signaling cascade.Together these experiments are expected to uncover some of the rules and molecular mechanisms that govern spine dynamics in developing hippocampus, providing important information for a better under-standing of the pathogenesis of developmental neuropsychiatric disorders.
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