Hippocampal pyramidal cells in adult Fmr1 knockout mice exhibit an immature-appearing profile of dendritic spines

Grossman, Aaron W.; Elisseou, Nicholas M.; McKinney, Brandon C.; Greenough, William T.

doi:10.1016/j.brainres.2006.02.044

Cited by 170 publications

(173 citation statements)

References 29 publications

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“…Activation of Rac1 enhances excitatory synaptic transmission by recruiting AMPARs to synapses during spine formation (Wiens et al, 2005). It is well known that abnormal dendritic spines are one of the fragile X characteristics (Grossman et al, 2006), which may be related to altered Rac1 activation, as we have demonstrated in our results, the RAC1 protein is hyperactivated in the brain and testicles of the Fmr1-KO mouse.…”

Section: Discussionsupporting

confidence: 73%

α-Tocopherol Protects Against Oxidative Stress in the Fragile X Knockout Mouse: an Experimental Therapeutic Approach for the Fmr1 Deficiency

Diego-Otero¹,

Romero-Zerbo²,

Bekay

et al. 2008

Neuropsychopharmacol

119

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Fragile X syndrome is the most common genetic cause of mental disability. The mechanisms underlying the pathogenesis remain unclear and specific treatments are still under development. Previous studies have proposed an abnormal hypothalamic-pituitary-adrenal axis and high cortisol levels are demonstrated in the fragile X patients. Additionally, we have previously described that NADPH-oxidase activation leads to oxidative stress in the brain, representing a pathological mechanism in the fragile X mouse model. Fmr1-knockout mice develop an altered free radical production, abnormal glutathione homeostasis, high lipid and protein oxidation, accompanied by stressdependent behavioral abnormalities and pathological changes in the first months of postnatal life. Chronic pharmacological treatment with a-tocopherol reversed pathophysiological hallmarks including free radical overproduction, oxidative stress, Rac1 and a-PKC activation, macroorchidism, and also behavior and learning deficits. The restoration of the oxidative status in the fragile X mouse emerges as a new and promising approach for further therapeutic research in fragile X syndrome.

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Section: Discussionsupporting

confidence: 73%

α-Tocopherol Protects Against Oxidative Stress in the Fragile X Knockout Mouse: an Experimental Therapeutic Approach for the Fmr1 Deficiency

Diego-Otero¹,

Romero-Zerbo²,

Bekay

et al. 2008

Neuropsychopharmacol

119

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“…Here we specifically focused our analysis on the postsynaptic pool of proteins by investigating PSD preparations derived from the mouse brain. PSD fractions were selectively prepared from the neocortex and the hippocampus, respectively, brain regions in which the loss of FMRP causes abnormal dendritic spine development (51,(53)(54)(55) and impaired synaptic plasticity (8 -10, 50, 56 -59).…”

Section: Discussionmentioning

confidence: 99%

Fragile X Mental Retardation Protein Regulates the Levels of Scaffold Proteins and Glutamate Receptors in Postsynaptic Densities

Schütt¹,

Falley²,

Richter

et al. 2009

Journal of Biological Chemistry

134

115

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In humans, the functional loss of the fragile X mental retardation protein (FMRP) 2 causes the fragile X syndrome (FXS), a severe form of inherited mental retardation (1-4). In the brain of both humans and mice, FMRP deficiency results in a significant change in both dendritic spine morphology and synaptic function (5-9). FMRP is an RNA-binding protein that is thought to act primarily as a repressor of mRNA translation. Among other subcellular regions in neurons, FMRP appears to exercise this control function at postsynaptic sites. It has been hypothesized that in dendrites FMRP locally controls the synthesis of proteins, such as components of the postsynaptic density (PSD), which regulate both dendritic spine morphology and synaptic function (2, 9, 10). The PSD is a complex protein network lying underneath the postsynaptic membrane of excitatory synapses (11-13). It serves to cluster glutamate receptors and cell adhesion molecules, recruit signaling proteins, and anchor these components to the microfilament-based cytoskeleton in dendritic spines. To combine these functions, the central layers of the PSD consist of several scaffold proteins, such as members of the PSD-95, SAPAP/GKAP, and Shank/ProSAP families. Because of their capacity to directly interact with many different PSD components and to regulate the size and shape of dendritic spines, Shanks in particular are assumed to represent master scaffold proteins of the PSD (11). Activity-dependent changes in the PSD composition are thought to represent a molecular basis for most principal brain functions, including learning and memory. Several of these long term synaptic changes and learning paradigms critically depend on dendritic protein synthesis (14 -17). Interestingly, mRNAs encoding some of the central components of the PSD, such as Shank1-3, SAPAP3, PSD-95, and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor subunits (GluR), are present in dendrites (18 -23).As FMRP has been implicated in the local regulation of mRNA translation at synapses, one crucial question is as follows: which postsynaptic proteins are affected by the loss of FMRP in a quantitative manner and may thus contribute to abnormal dendritic spine morphology and impaired synaptic plasticity? To specifically address this question, we took advan-* This work was supported by the Deutsche Forschungsgemeinschaft Grants Ki488/2-6 (to S. K.) and KR 1321/4-1 (to H.-J. K. and S. K.) and Thyssen-Stiftung Az. 10.05.2.185 (to D. R. and S. K.

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“…Such developmental consequences could be caused either by elevated FMR1 mRNA (Tassone et al 2000a, b, c;Jacquemont et al 2003;Oostra and Willemsen 2003;Allen et al 2004;Hagerman and Hagerman 2004) or a mild reduction in FMRP as is known to occur in individuals with the premutation, especially with high CGG repeat numbers (Tassone et al 2000a,b,c;Kenneson et al 2001;Entezam et al 2007). We would expect lower FMRP to result in abnormally reduced pruning during development (Irwin et al 2000;Bagni and Greenough 2005;McKinney et al 2005;Grossman et al 2006) which would in theory result in larger and potentially more active hippocampi. It is possible that lowered FMRP and increased mRNA, which can co-occur in carriers with the premutation, are affecting hippocampal structure and function in different ways, complicating the picture and making molecular/fMRI associations difficult to clearly discern, especially in so small a sample.…”

Section: Discussionmentioning

confidence: 99%

Reduced Hippocampal Activation During Recall is Associated with Elevated FMR1 mRNA and Psychiatric Symptoms in Men with the Fragile X Premutation

Koldewyn

Hessl

Adams

et al. 2008

Brain Imaging and Behavior

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Recent studies reveal that young carriers of the fragile X premutation are at increased risk for psychiatric conditions, memory problems and executive deficits. Post mortem and structural MRI studies suggest the hippocampus is preferentially affected by the premutation. The current study utilized magnetic resonance imaging (MRI) to explore the relationship between hippocampal structure and function as well as molecular/genetic and psychiatric measures in men with the fragile X premutation. Although the groups did not differ in hippocampal volume, the premutation group showed reduced left hippocampal activation and increased right parietal activation during a recall task relative to controls. These results suggest that brain function underlying memory recall is affected by premutation status. Left hippocampal activation was negatively correlated with both FMR1 mRNA level and psychiatric symptomology in the premutation group. These associations support the theory that increased levels of FMR1 mRNA affect brain function and contribute to psychiatric symptoms.

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Hippocampal pyramidal cells in adult Fmr1 knockout mice exhibit an immature-appearing profile of dendritic spines

Cited by 170 publications

References 29 publications

α-Tocopherol Protects Against Oxidative Stress in the Fragile X Knockout Mouse: an Experimental Therapeutic Approach for the Fmr1 Deficiency

α-Tocopherol Protects Against Oxidative Stress in the Fragile X Knockout Mouse: an Experimental Therapeutic Approach for the Fmr1 Deficiency

Fragile X Mental Retardation Protein Regulates the Levels of Scaffold Proteins and Glutamate Receptors in Postsynaptic Densities

Reduced Hippocampal Activation During Recall is Associated with Elevated FMR1 mRNA and Psychiatric Symptoms in Men with the Fragile X Premutation

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