Pioneering Insights in Preclinical Fragile X Syndrome Research

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.
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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.

Electrophysiology and Biomarkers​

Fmr1 KO show increased BDNF levels in hippocampus.​
No changes in BDNF levels were seen in the cortex of Fmr1 KO mice when compared to WT mice.

Time course of the changes in responses recorded in CA1 area of hippocampus induced with an application of an mGluR agonist (S)-DHPG (100μM).

Summary of the data for the last 5 min of experiment. *p<0.05 compared to Fmr1 KO

Following a stable baseline and subsequent enhancement of tonic GABA currents by the d subunit-selective agonist THIP (gaboxadol, 1 mM; +THIP), tonic currents were unmasked by blocking GABAA receptors with 100 mM picrotoxin.

Enhancement of tonic current by application of THIP normalized to baseline

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