The fragile X premutation is a tandem CGG trinucleotide repeat expansion in the fragile X mental retardation 1 (FMR1) gene between 55 and 200 repeats in length. A CGG knock-in (CGG KI) mouse has been developed that models the neuropathology and cognitive deficits reported in fragile X premutation carriers. It has been suggested that carriers of the premutation demonstrate a spatiotemporal hypergranularity, or reduced resolution of spatial and temporal processing. A temporal ordering of spatial locations task was used to evaluate the ability of CGG KI mice to process temporal and spatial information with either high or low levels of spatial interference. The results indicate that CGG KI mice showed difficulty performing a spatial novelty detection task when there were high levels of spatial interference, but were able to perform the novelty detection task when there was low spatial interference. These data suggest that CGG KI mice show reduced spatial and temporal resolution that are modulated by the dosage of the Fmr1 gene mutation, such that when behavioral tasks require mice to overcome high levels of either spatial or temporal interference, the CGG KI mice perform increasingly poorly as the CGG repeat length increases.
"FMR1-KO mice exhibit several phenotypical abnormalities also observed in the human disease such as enlarged testes in males and long, thin dendritic spines  . Cognitive deficits have been demonstrated through mildly impaired performance on the Morris water maze and spatial learning tests    . To date, the neurological deficits these mice incur have not been studied. "
[Show abstract][Hide abstract] ABSTRACT: Fragile X syndrome is the most common form of inherited mental retardation affecting up to 1 in 4000 individuals. The syndrome is induced by a mutation in the FMR1 gene, causing a deficiency in its gene by-product FMRP. Impairment in the normal functioning of FMRP leads to learning and memory deficits and heightened sensitivity to sensory stimuli, including sound (hyperacusis). The molecular basis of fragile X syndrome is thoroughly understood; however, the neural mechanisms underlying hyperacusis have not yet been determined. As the inferior colliculus (IC) is the principal midbrain nucleus of the auditory pathway, the current study addresses the questions underlying the neural mechanism of hyperacusis within the IC of fragile X mice. Acute experiments were performed in which electrophysiological recordings of the IC in FMR1-KO and WT mice were measured. Results showed that Q-values for WT were significantly larger than that of FMR-1 KO mice, indicating that WT mice exhibit sharper tuning curves than FMR1-KO mice. We also found the ratio of the monotonic neurons in the KO mice was much higher than the WT mice. These results suggest that lack of FMRP in the auditory system affects the developmental maturation and function of structures within the auditory pathway, and in this case specifically the IC. The dysfunction observed within the auditory neural pathway and in particular the IC may be related to the increased susceptibility to sound as seen in individuals with fragile X syndrome. Our study may help on understanding the mechanisms of the fragile X syndrome and hyperacusis.
"For example, adult fXPCs have impairments on tasks that rely on the M pathway, but not on tasks that rely on the P pathway [43-45]. A mouse model of fXPC shows impaired memory for spatial locations , temporal order , and temporal order of spatial locations . Whereas younger fXPC mice were impaired in detecting a change in distance between two objects, but not in detecting a transposition of objects, older fXPC mice were impaired in both tasks. "
[Show abstract][Hide abstract] ABSTRACT: Background
A previous study reported enhanced psychomotor speed, and subtle but significant cognitive impairments, modulated by age and by mutations in the fragile X mental retardation 1 (FMR1) gene in adult female fragile X premutation carriers (fXPCs). Because male carriers, unlike females, do not have a second, unaffected FMR1 allele, male fXPCs should exhibit similar, if not worse, impairments. Understanding male fXPCs is of particular significance because of their increased risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS).
Male fXPCs (n = 18) and healthy control (HC) adults (n = 26) aged less than 45 years performed two psychomotor speed tasks (manual and oral) and two visuospatial tasks (magnitude comparison and enumeration). In the magnitude comparison task, participants were asked to compare and judge which of two bars was larger. In the enumeration task, participants were shown between one and eight green bars in the center of the screen, and asked to state the total number displayed. Enumeration typically proceeds in one of two modes: subitizing, a fast and accurate process that works only with a small set of items, and counting, which requires accurate serial-object detection and individuation during visual search. We examined the associations between the performance on all tasks and the age, full-scale intelligent quotient, and CGG repeat length of participants.
We found that in the magnitude comparison and enumeration tasks, male fXPCs exhibited slower reaction times relative to HCs, even after controlling for simple reaction time.
Our results indicate that male fXPCs as a group show impairments (slower reaction times) in numerical visuospatial tasks, which are consistent with previous findings. This adds to a growing body of literature characterizing the phenotype in fXPCs who are asymptomatic for FXTAS. Future longitudinal studies are needed to determine how these impairments relate to risk of developing FXTAS.
[Show abstract][Hide abstract] ABSTRACT: It has become increasingly important that the field of behavioral genetics identifies not only the gross behavioral phenotypes associated with a given mutation, but also the behavioral endophenotypes that scale with the dosage of the particular mutation being studied. Over the past few years, studies evaluating the effects of the polymorphic CGG trinucleotide repeat on the
FMR1 gene underlying Fragile X-Associated Disorders have reported preliminary evidence for a behavioral endophenotype in human Fragile X Premutation carrier populations as well as the CGG knock-in (KI) mouse model. More recently, the behavioral experiments used to test the CGG KI mouse model have been extended to the
Fmr1 knock-out (KO) mouse model. When combined, these data provide compelling evidence for a clear neurocognitive endophenotype in the mouse models of Fragile X-Associated Disorders such that behavioral deficits scale predictably with genetic dosage. Similarly, it appears that the CGG KI mouse effectively models the histopathology in Fragile X-Associated Disorders across CGG repeats well into the full mutation range, resulting in a reliable histopathological endophenotype. These endophenotypes may influence future research directions into treatment strategies for not only Fragile X Syndrome, but also the Fragile X Premutation and Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).
F1000 Research 12/2013; 2:287. DOI:10.12688/f1000research.2-287.v1
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