Synaptic plasticity; synaptogenesis; development; mental retardation; hippocampus; plasticity; brain networks; learning and memory
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.
Caroni P., Donato F., Muller D. (2012), Structural plasticity upon learning: regulation and functions, in Nat. Rev. Neurosci
, 13, 478-490.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Dubos Aline, Alteration of synaptic network dynamics by the intellectual disability protein PAK3, in J. Neurosci
Mendez Pablo, Garcia-Segura Luis Miguel, Muller Dominique, Estradiol promotes spine growth and synapse formation without affecting pre-established networks., in Hippocampus
Poglia Lorenzo, Muller Dominique, Nikonenko Irina, Ultrastructural modifications of spine and synapse morphology by SAP97., in Hippocampus
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.