Genetic-Background Modulation of Core and Variable Autistic-Like Symptoms in Fmr1 Knock-Out Mice

Abstract

BackgroundNo animal models of autism spectrum disorders (ASD) with good construct validity are currently available; using genetic models of pathologies characterized by ASD-like deficits, but with known causes, may be therefore a promising strategy. The Fmr1-KO mouse is an example of this approach, modeling Fragile X syndrome, a well-known genetic disorder presenting ASD symptoms. The Fmr1-KO is available on different genetic backgrounds (FVB versus C57BL/6), which may explain some of the conflicting results that have been obtained with these mutants up till now.Methods Fmr1 KO and their wild-type littermates on both the FVB and C57BL/6 genetic backgrounds were examined on a battery of tests modeling the clinical symptoms of ASD, including the triad of core symptoms (alterations in social interaction and communication, presence of repetitive behaviors), as well as the secondary symptoms (disturbances in sensori-motor reactivity and in circadian patterns of activity, epileptic events).Results Fmr1-KO mice displayed autistic-like core symptoms of altered social interaction and occurrence of repetitive behaviors with additional hyperactivity. The genetic background modulated the effects of the Fmr1 deletion and it appears that the C57BL/6 background may be more suitable for further research on core autistic-like symptoms.ConclusionsThe Fmr1-mouse line does not recapitulate all of the main core and secondary ASD symptoms, but still can be useful to elucidate the neurobiological mechanisms underlying specific ASD-like endophenotypes.

Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons

“…4 B-D and Fig. S4 D-G), all striatal-dependent symptoms observed in Fmr1 −/y mice (25)(26)(27)(28). Stereotypic behavior is indicated by an enhanced learning on the accelerating rotarod (24), mainly at late stages of learning (Fig.…”

Modeling fragile X syndrome in the <i>Fmr1</i> knockout mouse

“…Additionally, Fmr1 KO performance was disrupted by olfactory distracters, with mutant mice making more inaccurate responses during distracter presentations (122). A consistent behavioral finding in Fmr1 KO mice is their increased locomotor activity compared to wildtype controls in the open field test (48,52,89,90,(123)(124)(125)(126)(127)(128)(129)(130). It is important to note that the robust hyperactivity phenotype seen in Fmr1 KO mice could be a confounding factor for the assessment of sustained attention, given that the general activity of mutant mice may interfere with task engagement.…”

“…In the five-choice serial reaction time task, Fmr1 KO mice demonstrated heightened perseveration and responding during novel rule acquisition, which normalized with training (119). Fmr1 KO mice also exhibited higher levels of self-grooming, a repetitive behavior, than wildtype controls (89,133). Additionally, Fmr1 KO mice buried more marbles in the marble burying test (93,107,124), a measure of repetitive behavior (134).…”

“…These data suggest that FMRP expression is necessary for the development of normal dendritic spine morphology, and that the loss of FMRP negatively impacts the physical structure of the synapse. (89,107). Explanations for the divergent findings on PPI in Fmr1 mice reported by different laboratories include use of different murine genetic backgrounds and differences in testing protocols (111).…”

“…Seizures associated with FXS are infrequent, are often partial, and are typically controlled with medications (82,83). Fmr1 KO mice have not been reported to display spontaneous seizures, but are more susceptible to audiogenic seizures, induced by exposure to a 125 decibel, high-intensity siren (48,81,(84)(85)(86)(87)(88)(89)(90)(91)(92)(93). Audiogenic seizure vulnerability in Fmr1 KO mice may reflect seizure susceptibly in FXS, although audiogenic seizure severity in Fmr1 KO mice varied in degree depending on age and background strain (86,91,94,95).…”