Defective synaptic transmission and structure in the dentate gyrus and selective fear memory impairment in the Rsk2 mutant mouse model of Coffin-Lowry syndrome

被引:24
作者
Morice, Elise [1 ,2 ]
Farley, Severine [1 ,2 ]
Poirier, Roseline [1 ,2 ]
Dallerac, Glenn [1 ,2 ]
Chagneau, Carine [1 ,2 ]
Pannetier, Solange [3 ]
Hanauer, Andre [3 ]
Davis, Sabrina [1 ,2 ]
Vaillend, Cyrille [1 ,2 ]
Laroche, Serge [1 ,2 ]
机构
[1] CNRS, Ctr Neurosci Paris Sud, UMR 8195, F-91405 Orsay, France
[2] Univ Paris 11, UMR 8195, F-91405 Orsay, France
[3] Univ Strasbourg 1, CNRS, INSERM, Inst Genet & Biol Mol & Cellulaire, F-67404 Illkirch Graffenstaden, France
关键词
Intellectual disability; Mental retardation; Coffin-Lowry; Hippocampus; Trace fear conditioning; Reconsolidation; Synaptic plasticity; Synaptic morphology; Transcription factors; LONG-TERM POTENTIATION; ELEMENT-BINDING PROTEIN; POSTSYNAPTIC DENSITY; DENDRITIC SPINES; REGULATED KINASE; CALCIUM SIGNALS; GENE-EXPRESSION; MRSK2-KO MOUSE; SHANK FAMILY; PLASTICITY;
D O I
10.1016/j.nbd.2013.05.016
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The Coffin-Lowry syndrome (CIS) is a syndromic form of intellectual disability caused by loss-of-function of the RSK2 serine/threonine kinase encoded by the rsk2 gene. Rsk2 knockout mice, a murine model of CLS, exhibit spatial learning and memory impairments, yet the underlying neural mechanisms are unknown. In the current study, we examined the performance of Rsk2 knockout mice in cued, trace and contextual fear memory paradigms and identified selective deficits in the consolidation and reconsolidation of hippocampal-dependent fear memories as task difficulty and hippocampal demand increase. Electrophysiological, biochemical and electron microscopy analyses were carried out in the dentate gyrus of the hippocampus to explore potential alterations in neuronal functions and structure. In vivo and in vitro electrophysiology revealed impaired synaptic transmission, decreased network excitability and reduced AMPA and NMDA conductance in Rsk2 knockout mice. In the absence of RSK2, standard measures of short-term and long-term potentiation (LIP) were normal, however LIP-induced CREB phosphorylation and expression of the transcription factors EGR1/ZIF268 were reduced and that of the scaffolding protein SHANK3 was blocked, indicating impaired activity-dependent gene regulation. At the structural level, the density of perforated and non-perforated synapses and of multiple spine boutons was not altered, however, a clear enlargement of spine neck width and postsynaptic densities indicates altered synapse ultrastructure. These findings show that RSK2 loss-of-function is associated in the dentate gyrus with multi-level alterations that encompass modifications of glutamate receptor channel properties, synaptic transmission, plasticity-associated gene expression and spine morphology, providing novel insights into the mechanisms contributing to cognitive impairments in CLS. (C) 2013 Elsevier Inc. All rights reserved.
引用
收藏
页码:156 / 168
页数:13
相关论文
共 88 条
  • [1] Mechanisms of memory stabilization: are consolidation and reconsolidation similar or distinct processes?
    Alberini, CM
    [J]. TRENDS IN NEUROSCIENCES, 2005, 28 (01) : 51 - 56
  • [2] Anatomical and physiological plasticity of dendritic spines
    Alvarez, Veronica A.
    Sabatini, Bernardo L.
    [J]. ANNUAL REVIEW OF NEUROSCIENCE, 2007, 30 : 79 - 97
  • [3] Anagnostaras SG, 2001, HIPPOCAMPUS, V11, P8
  • [4] The RSK family of kinases: emerging roles in cellular signalling
    Anjum, Rana
    Blenis, John
    [J]. NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2008, 9 (10) : 747 - 758
  • [5] Mitogen- and stress-activated protein kinase 1 mediates cAMP response element-binding protein phosphorylation and activation by neurotrophins
    Arthur, JSC
    Fong, AL
    Dwyer, JM
    Davare, M
    Reese, E
    Obrietan, K
    Impey, S
    [J]. JOURNAL OF NEUROSCIENCE, 2004, 24 (18) : 4324 - 4332
  • [6] Reconsolidation of memory: A decade of debate
    Besnard, Antoine
    Caboche, Jocelyne
    Laroche, Serge
    [J]. PROGRESS IN NEUROBIOLOGY, 2012, 99 (01) : 61 - 80
  • [7] Do thin spines learn to be mushroom spines that remember?
    Bourne, Jennifer
    Harris, Kristen M.
    [J]. CURRENT OPINION IN NEUROBIOLOGY, 2007, 17 (03) : 381 - 386
  • [8] DEFICIENT LONG-TERM-MEMORY IN MICE WITH A TARGETED MUTATION OF THE CAMP-RESPONSIVE ELEMENT-BINDING PROTEIN
    BOURTCHULADZE, R
    FRENGUELLI, B
    BLENDY, J
    CIOFFI, D
    SCHUTZ, G
    SILVA, AJ
    [J]. CELL, 1994, 79 (01) : 59 - 68
  • [9] MAPK, CREB and zif268 are all required for the consolidation of recognition memory
    Bozon, B
    Kelly, A
    Josselyn, SA
    Silva, AJ
    Davis, S
    Laroche, S
    [J]. PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, 2003, 358 (1432) : 805 - 814
  • [10] RSK2 signaling in brain habenula contributes to place aversion learning
    Darcq, Emmanuel
    Koebel, Pascale
    Del Boca, Carolina
    Pannetier, Solange
    Kirstetter, Anne-Sophie
    Garnier, Jean-Marie
    Hanauer, Andre
    Befort, Katia
    Kieffer, Brigitte L.
    [J]. LEARNING & MEMORY, 2011, 18 (09) : 574 - 578