Long‐term potentiation in the hippocampus of fragile X knockout mice

Godfraind, Jean‐Marie; Reyniers, Edwin; Boulle, Kristel De; D’Hooge, Rudi; Deyn, Peter Paul De; Bakker, Cathy; Oostra, Ben A.; Kooy, R. Frank; Willems, Patrick J.

doi:10.1002/(sici)1096-8628(19960809)64:2<246::aid-ajmg2>3.3.co;2-h

Cited by 50 publications

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“…Although it is consistently reported that LTD is exaggerated in hippocampus (Huber et al, 2002;Zhang et al, 2009) and cerebellum (Koekkoek et al, 2005), LTP impairment depends on the region of the brain as well as the induction protocols. Some reports find that LTP is not affected in the hippocampus (Bear et al, 2004;Godfraind et al, 1996;Paradee et al, 1999;Zhang et al, 2009), whereas others show that LTP is reduced in the hippocampus (Hu et al, 2008;Larson et al, 2005;Lauterborn et al, 2007;Lee et al, 2011;Shang et al, 2009). In the ACC, we reported that the early phase of LTP was impaired in cingulate pyramidal cells (Zhao et al, 2005a).…”

Section: Fmr1 Ko Mice Exhibited Reduced L-ltp In the Accmentioning

confidence: 63%

“…To date, most LTP studies have been focusing on the hippocampus of Fmr1 KO mice. In the hippocampus, some studies show that LTP is intact (Auerbach and Bear, 2010;Bear et al, 2004;Godfraind et al, 1996;Paradee et al, 1999), whereas others confirm the deficit of LTP by using different LTP induction protocols (Hu et al, 2008;Lauterborn et al, 2007;Lee et al, 2011;Shang et al, 2009). Furthermore, L-LTP of the hippocampus was found to be normal in Fmr1 KO mice (Zhang et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome

Chen

Song

et al. 2014

Neuropsychopharmacol

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Fragile X syndrome, caused by the mutation of the Fmr1 gene, is characterized by deficits of attention and learning ability. In the hippocampus of Fmr1 knockout mice (KO), long-term depression is enhanced whereas long-term potentiation (LTP) including late-phase LTP (L-LTP) is reduced or unaffected. Here we examined L-LTP in the anterior cingulate cortex (ACC) in Fmr1 KO mice by using a 64-electrode array recording system. In wild-type mice, theta-burst stimulation induced L-LTP that does not occur in all active electrodes/ channels within the cingulate circuit and is typically detected in B75% of active channels. Furthermore, L-LTP recruited new responses from previous inactive channels. Both L-LTP and the recruitment of inactive responses were blocked in the ACC slices of Fmr1 KO mice. Bath application of metabotropic glutamate receptor 5 (mGluR5) antagonist or glycogen synthase kinase-3 (GSK3) inhibitors rescued the L-LTP and network recruitment. Our results demonstrate that loss of FMRP will greatly impair L-LTP and recruitment of cortical network in the ACC that can be rescued by pharmacological inhibition of mGluR5 or GSK3. This study is the first report of the network properties of L-LTP in the ACC, and provides basic mechanisms for future treatment of cortex-related cognitive defects in fragile X patients.

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Section: Fmr1 Ko Mice Exhibited Reduced L-ltp In the Accmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome

Chen

Song

et al. 2014

Neuropsychopharmacol

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“…Initial electrophysiological studies examining the NMDA receptor-dependent LTP in the hippocampus did not find a difference in early-or late-phase LTP between wild-type and Fmr1 knockout mice (Godfraind et al, 1996;Paradee et al, 1999). Interestingly, it was Figure 3.…”

Section: The Mouse Model and Molecular Mechanisms Of Fragile X Syndromementioning

confidence: 97%

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

et al. 2010

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The purpose of this study was to examine the expression of GABAergic proteins in Fmr1 knockout mice during brain maturation and to assess behavioural changes potentially linked to perturbations in the GABAergic system. Quantitative western blotting of the forebrain revealed that compared to wild-type mice, the GABA A receptor α1, β2, and δ subunits, and the GABA catabolic enzymes GABA transaminase and SSADH were down-regulated during postnatal development, while GAD65 was up-regulated in the adult knockout mouse forebrain. In tests of locomotor activity, the suppressive effect on motor activity of the GABA A β2/3 subunit-selective drug loreclezole was impaired in the mutant mice. In addition, sleep time induced by the GABA A β2/3-selective anaesthetic drug etomidate was decreased in the knockout mice. Our results indicate that disruptions in the GABAergic system in the developing brain may result in behavioural consequences in adults with fragile X syndrome.iii

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“…There are two wellstudied forms of LTD, N-methyl-D-aspartate receptormediated LTD (NMDAR-LTD) and mGluR-LTD [54]. Although LTP is unaffected in the hippocampus of Fmr1-knockout mice, mGluR-LTD, but not NMDAR-LTD, is significantly altered [53,55]. Using two distinct induction protocols (synaptic stimulation and induction by the highly specific group 1 mGluR agonist DHPG), it was found that mGluR-LTD is significantly increased in the hippocampus of Fmr1-knockout mice.…”

Section: How Does Fmrp Perform This Role?mentioning

confidence: 99%

New insights into fragile X syndrome: from molecules to neurobehaviors

Jin

Warren

2003

Trends in Biochemical Sciences

190

124

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Fragile X syndrome -a common form of inherited mental retardation -is caused by the loss of the fragile X mental retardation 1 protein (FMRP). FMRP is an RNA-binding protein which forms a messenger ribonucleoprotein (mRNP) complex that associates with translating polyribosomes. It has been proposed that FMRP is involved in synaptic plasticity through the regulation of mRNA transportation and translation. Recent advances in the identification of the mRNA ligands that are bound by FMRP, the RNA sequence and structure required for FMRP -RNA interaction, and the physiological consequences of FMRP deficiency in the brain are important steps towards understanding the molecular pathogenesis of fragile X syndrome, and learning and memory in general.Fragile X syndrome is the most common form of inherited mental retardation, with the estimated prevalence of one in 4000 males and one in 8000 females. In addition to cognitive deficits, the phenotype of fragile X syndrome includes mildly abnormal facial features (a prominent jaw, high forehead and large ears), MACROORCHIDISM (see Glossary) in postpubescent males and subtle connective tissue abnormalities [1]. Many patients also manifest attention-deficit hyperactivity disorder and autistic-like behavior. As one of the first identified human disorders caused by trinucleotide repeat expansion, fragile X syndrome is the result of a massive CGG trinucleotide repeat expansion within the gene fragile X mental retardation 1 (FMR1). FMR1 is a highly conserved gene that consists of 17 exons, and spans , 38 kilobases (kb). Within the 4.4-kb FMR1 transcript, a CGG trinucleotide repeat is located in the 5 0 untranslated region (UTR) [2]. Among normal individuals, this CGG repeat is highly polymorphic in length and content, often punctuated by AGG interruptions. The normal repeat size ranges from 7 to , 54, with 30 repeats found in the most common allele. In most affected individuals, CGG repeats are massively expanded over 230 repeats (full mutation) and become abnormally hypermethylated, which results in the transcriptional silencing of FMR1 [1]. Identification of other mutations in FMR1 (e.g. deletions and a point mutation among patients with the typical phenotype, but without FRAGILE SITE expression) has confirmed that the FMR1 gene is the only gene involved in the pathogenesis of fragile X syndrome and the loss of FMR1 product -fragile X mental retardation protein (FMRP) -causes fragile X syndrome [1]. A mouse model of fragile X syndrome was created using gene targeting; the Fmr1-knockout mice exhibit macroorchidism and subtle deficits in learning and memory, which mimic the human phenotype [3].In this review, we discuss the recent progress in understanding the biological functions of FMRP and the physiological consequences of its absence that lead to mental retardation. Features of FMRPFMRP is widely expressed in fetal and adult tissues, with the most abundant expression in brain and testes [4]. FMRP, and its autosomal paralogs the fragile-X-related protein FXR1P and FXR2P, consist...

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Long‐term potentiation in the hippocampus of fragile X knockout mice

Cited by 50 publications

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Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome

Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

New insights into fragile X syndrome: from molecules to neurobehaviors

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