NMDA receptor hypofunction in the dentate gyrus and impaired context discrimination in adult <i>Fmr1</i> knockout mice

Eadie, Brennan D.; Cushman, Jesse D.; Kannangara, Timal S.; Fanselow, Michael S.; Christie, Brian R.

doi:10.1002/hipo.20890

Cited by 95 publications

(95 citation statements)

References 41 publications

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“…Fmr1 KO mice model the most common cause of inherited ID (1), but their cognitive impairments are subtle and inconsistently observed (19,21,30). As increased anxiety likely disrupts performance in many tasks (31), we sought a low-stress paradigm in which the KOs have a robust memory impairment.…”

Section: Discussionmentioning

confidence: 99%

“…We focused on OLM because its retrieval depends on hippocampal field CA1 (11,14), which exhibits an elevated LTP threshold in Fmr1 KOs (7,8) and enhanced potentiation with spaced stimulation in WTs (10,17). However, Fmr1 KOs have more robust LTP impairments in other regions including cortex (6,(18)(19)(20)(21). Therefore, we tested if the KOs have deficits in enduring NOR memory which depends, at least in part, on perirhinal and insular cortices for retrieval (14,22,23).…”

Section: Significancementioning

confidence: 99%

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Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice

Seese

Wang

Yao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Recent studies have shown that short, spaced trains of afferent stimulation produce much greater long-term potentiation (LTP) than that obtained with a single, prolonged stimulation episode. The present studies demonstrate that spaced training regimens, based on these LTP timing rules, facilitate learning in wild-type (WT) mice and can offset learning and synaptic signaling impairments in the fragile X mental retardation 1 (Fmr1) knockout (KO) model of fragile X syndrome. We determined that 5 min of continuous training supports object location memory (OLM) in WT but not Fmr1 KO mice. However, the same amount of training distributed across three short trials, spaced by one hour, produced robust long-term memory in the KOs. At least three training trials were needed to realize the benefit of spacing, and intertrial intervals shorter or longer than 60 min were ineffective. Multiple short training trials also rescued novel object recognition in Fmr1 KOs. The spacing effect was surprisingly potent: just 1 min of OLM training, distributed across three trials, supported robust memory in both genotypes. Spacing also rescued training-induced activation of synaptic ERK1/2 in dorsal hippocampus of Fmr1 KO mice. These results show that a spaced training regimen designed to maximize synaptic potentiation facilitates recognition memory in WT mice and can offset synaptic signaling and memory impairments in a model of congenital intellectual disability.Fmr1 KO | hippocampus | object location memory | massed training | novel object recognition F ragile X syndrome (FXS) is the most common cause of inherited intellectual disability (ID) (1). Currently no treatments exist for cognitive deficits associated with FXS or other neurodevelopmental disorders with ID. Research on the fragile X mental retardation 1 (Fmr1) KO mouse model of FXS has identified impairments in synaptic signaling required to produce lasting synaptic modifications (2-6) with corresponding disturbances in the activation threshold and stabilization of hippocampal long-term potentiation (LTP) (7,8). These findings suggest specific synaptic disturbances underlie learning problems in FXS as well as targets for therapeutic interventions to improve cognitive function.The present experiments tested predictions from LTP studies as to how modified training paradigms might rescue synaptic signaling and learning in Fmr1 KO mice. There is a deep literature demonstrating that individuals learn better when trained in short trials spaced in time than in a single, extended training episode (9). We recently found that LTP exhibits a synaptic analog for this "spaced trials effect" (10). Specifically, in hippocampal field CA1 short trains of theta burst afferent stimulation spaced by 60 min elicit far greater synaptic potentiation than can be achieved with long theta trains or by repeated trains applied at shorter intervals. As LTP is considered a mechanism of memory encoding, we propose that spaced training regimens that use the same 60-min periodicity should facilitate hippocampus...

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Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice

Seese

Wang

Yao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…FMRP activity is regulated in response to metabotropic glutamate receptors (mGluRs) (78), 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptors (79), γ-aminobutyric acid (GABA) receptors (76,80,81), N-methyl-d-aspartate (NMDA) receptors (82)(83)(84), and the tyrosine kinase or BDNF/NT-3 growth factor (TrkB) receptors (85). Upon receptor activation, the FMRPmediated translational block is released, possibly due to changes (86) in its phosphorylation status, and protein synthesis can ensue.…”

Section: Figurementioning

confidence: 99%

Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics

Bagni¹,

Tassone²,

Neri³

et al. 2012

J. Clin. Invest.

297

289

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Genetics of fragile XFragile X syndrome (FXS), an X-linked condition first described by Martin and Bell (1), is the leading cause of inherited intellectual disability (ID). Estimates report that FXS affects approximately 1 in 2,500 to 5,000 men and 1 in 4,000 to 6,000 women (2, 3). FXS is caused by mutations in the FMR1 gene, which is located on the X chromosome and whose locus at Xq27.3 coincides with the folate-sensitive fragile site (4, 5). Cytogenetic methods (6) used in the past to diagnose FXS have been replaced by molecular diagnostic of FMR1 DNA using Southern blot analysis and, more recently, PCR.Affected men display varying degrees of symptoms ranging from mild to severe. Due to compensation by the unaffected X chromosome, only one-third of female carriers with a full mutation (FM) have ID; the majority have normal IQ, although learning difficulties and emotional problems are common (7).Identified in 1991 by positional cloning (8), the FMR1 gene is characterized by the presence of a polymorphic CGG triplet sequence in the 5′ UTR (8, 9). Expansion in this triplet sequence gives rise to FXS, which is the prototype of unstable triplet expansion disorders. The triplet variability defines four types of alleles (Figure 1). Normal alleles have a number of CGG repeats, ranging from 5 to 54, with a mode of 30. Premutation (PM) alleles have a number of CGG repeats, ranging from 55 to 200. PM alleles are unstable and have a strong tendency to expand to FM alleles upon maternal transmission. Expansion from a PM to FM can occur with alleles as small as 56 CGGs (10). Alleles possessing between 45 and 54 CGG repeats, referred to as gray-zone or intermediate alleles, are proposed to be precursors of PM alleles, potentially due to paternal and maternal meiotic instability (11). The risk of a PM to FM transition depends on the CGG repeat size, such that the expansion risk is nearly 100% for alleles of >99 CGG repeats (11). A recent study (12) showed that the number of AGG interruptions present in the CGG repeats correlates inversely with the risk of expansion to a FM in the next generation. The presence of AGG interruptions, in addition to the CGG length, may thus better define the risk for transmission from a maternal PM to FM in the offspring.FMR1 silencing is the consequence of rather complex epigenetic modifications (13). In FXS, cytosines located approximately up to 1-kb upstream of the CGG repeat sequences, including the FMR1 promoter, are methylated (14, 15). Normal alleles are also methylated in the FMR1 promoter region but not in close proximity to the CGG repeat, which seems to be a "boundary" in the normal allele that prevents methylation from spreading. This boundary is missing in FM alleles, and the cytosines upstream of the CGG repeat become methylated around the thirteenth week of embryonic development (16). As a consequence, gene transcription is inhibited, leading to the absence of its protein product FMRP (17). Of note, some alleles remain partially or even fully unmethylated (UFM), despite containing ...

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“…In the Fmr1 KO mice, LTP has been found altered in hippocampus only after theta burst stimulation (Lauterborn et al 2007), a stimulation able to induce LTP in close resemblance to physiological hippocampal frequency of theta rhythm (5-10 Hz) (Capocchi et al 1992). Only recently, a reduction of LTP in dentate gyrus has been observed in Fmr1 KO mice possibly due to a reduction of NMDA excitatory postsynaptic currents (EPSCs), which is a consequence of a reduced ratio of NMDA/AMPA receptors (Eadie et al 2010;Yun and Trommer 2011). On the other hand, high-frequency stimulation (100-400 Hz) does not affect LTP in hippocampus of Fmr1 KO mice (Godfraind et al 1996;Li et al 2002;Paradee et al 1999;Zhang et al 2009).…”

Section: Electrophysiological Phenotypesmentioning

confidence: 99%

Molecular and Cellular Aspects of Mental Retardation in the Fragile X Syndrome: From Gene Mutation/s to Spine Dysmorphogenesis

Rubeis

Fernández

Buzzi

et al. 2012

Synaptic Plasticity

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The Fragile X syndrome (FXS) is the most frequent form of inherited mental retardation and also considered a monogenic cause of Autism Spectrum Disorder. FXS symptoms include neurodevelopmental delay, anxiety, hyperactivity, and autistic-like behavior. The disease is due to mutations or loss of the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein abundant in the brain and gonads, the two organs mainly affected in FXS patients. FMRP has multiple functions in RNA metabolism, including mRNA decay, dendritic targeting of mRNAs, and protein synthesis. In neurons lacking FMRP, a wide array of mRNAs encoding proteins involved in synaptic structure and function are altered. As a result of this complex dysregulation, in the absence of FMRP, spine morphology and functioning is impaired. Consistently, model organisms for the study of the syndrome recapitulate the phenotype observed in FXS patients, such as dendritic spine anomalies and defects in learning. Here, we review the fundamentals of genetic and clinical aspects of FXS, devoting a specific attention to ASD comorbidity and FXS-related diseases. We also review the current knowledge on FMRP functions through structural, molecular, and cellular findings. Finally, we discuss the neuroanatomical, electrophysiological, and behavioral defects caused by FMRP loss, as well as the current treatments able to partially revert some of the FXS abnormalities.

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NMDA receptor hypofunction in the dentate gyrus and impaired context discrimination in adult Fmr1 knockout mice

Cited by 95 publications

References 41 publications

Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice

Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice

Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics

Molecular and Cellular Aspects of Mental Retardation in the Fragile X Syndrome: From Gene Mutation/s to Spine Dysmorphogenesis

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