Fragile X syndrome is a genetic disorder caused by a CGG expansion in the FMR1 gene. This condition tends to affect males more severely, while females often present a mosaic pattern of effects, meaning the severity can vary widely among individuals. Fragile X syndrome has been identified as a potential cause of autism or related disorders, though it’s important to note that not all children diagnosed with Fragile X syndrome will experience these conditions.
Symptoms include:
- Developmental delays: crawling, walking
- Hand clapping or hand biting
- Hyperactive or impulsive behavior
- Mental retardation
- Speech and language delay
- Tendency to avoid eye contact
- Physical signs: Flat feet, flexible joints and low muscle tone, large body size, large forehead or ears with a prominent jaw, long face, large testicles, soft skin
The FMR1 KO Mouse Model
These mice have a knockout allele of the Fragile X mental retardation syndrome 1 gene (Fmr1) on the X chromosome and exhibit many phenotypic characteristics of the Fragile X Syndrome in humans, including hyperactivity, repetitive behavior, and seizures. This genetic modification results in the absence of the Fragile X mental retardation protein (FMRP), a change that triggers the activation of the RAC1 protein. The consequence of this activation is a series of abnormalities in dendritic spines across various brain regions, leading to altered synaptic function. These alterations are pivotal in understanding the neurobiological underpinnings of Fragile X syndrome, as they provide insight into the disorder’s impact on neuronal architecture and connectivity.
The lack of FMRP in these mice not only affects the physical structure of neurons but also significantly alters synaptic plasticity. This alteration manifests as impaired long-term potentiation in the cortex and hippocampus, alongside an increased long-term depression in both the hippocampus and cerebellum. Such changes in synaptic behavior are essential for understanding the learning and memory deficits associated with Fragile X syndrome. Male FMR1 knockout (KO) mice, particularly those bred on an FVB/n background at PsychoGenics, are extensively utilized in research studies. They offer a valuable tool for exploring the mechanisms of Fragile X syndrome and developing potential therapeutic strategies to mitigate its effects.
No difference in body weight between Fmr1 KO and WT mice.
Fmr1 KO mice show hyperactivity in the open field test at 10 and 14 weeks of age.
Rearing Activity: Fmr1 KO mice show increased rearing activity in the open field test at 10 and 14 weeks of age.
Fmr1 KO mice spend more time in the center of the open field at 10 and 14 weeks of age.
Electrophysiology and Biomarkers
Long-Term Depression: Fmr1 KO mice exhibit enhanced hippocampal mGluR-dependent long-term potentiation (LTD), which is reversed by mGluR antagonist 8-OH-DPAT.
A shift in the balance of excitatory/inhibitory neurotransmission is thought to underlie many of the behavioral phenotypes in Fragile X, including hyperactivity, sensory hypersensitivity, and seizures. A significant reduction in tonic inhibitory currents, a critical factor modulating neuronal excitability, was observed in dentate granule cells of 2-month-old male mice.
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