Fragile X Syndrome

Fragile X syndrome is caused by mutations of the FMR1 gene, leading to loss of functional fragile x mental retardation protein (FMRP). FXS is characterised by delays in neurodevelopmental milestones, autistic behaviour, anxiety, and cognitive deficits. Notably, anxiety and cognitive deficits are affected by multiple sensory systems, which on the brain-level includes an abnormal sensory processing, hypersensitivity and reduced habituation to repeated sensory stimuli. Preclinical and clinical research is focused on targeting all FXS symptoms, to improve the quality of life of FXS patients.  

Preclinical Fragile X Syndrome research

Preclinical studies in the Fmr1 knock-out (KO) mouse model of FXS (1) have identified several compounds that rescue several FXS-related symptoms and reached clinical trials. However, the translation of these treatments to FXS patients has not yet been successful, with most of the compounds showing minimal to no improvement compared across various randomized-controlled trials (2). This highlights the need for more effective translational outcome measures, tested during the preclinical trial phase. Electro-encephalograms (EEG) recordings during sensory information processing are a promising translational outcome measure in Fmr1 KO mice (3,4).  

EEG as a translational biomarker for preclinical Fragile X Syndrome research

In FXS patients, brain abnormalities were identified through the observation of atypical event-related potential (ERP) responses shown during EEG recording (3). ERPs are subtle changes in electrical activity generated in response to specific motor, sensory, or cognitive events. In clinical research, ERPs are often studied using an auditory oddball paradigm, where participants listen to a series of regular tones with occasional different or “odd” tones. In response, the EEG recordings of the observed ERPs provide insights into auditory processing deficits in FXS patients (3). Interestingly, such auditory processing deficits have also been detected in the widely used Fmr1 KO mouse model (3,4). In turn, this may allow for greater translational outcomes during the preclinical stage, better predicting the clinical success of targeted FXS therapeutics.  

At InnoSer, we have developed a protocol to test this paradigm in Fmr1 KO mice, further shown in Figure 1. Briefly, this experiment is conducted in a sound attenuating chamber (1). Mouse is implanted with a wireless EEG recording system that also collects body movement (XYZ activity) (2) and placed in a Plexiglas cylinder (3). A speaker is set up with adjustable volume and frequency to generate specific acoustic stimuli (4). A recorder is placed inside the chamber to record the sound (5), together with the infrared light synchronisation pulse generator (6) to help synchronize the acoustic stimuli with the recorded EEG signals. Our internal data has shown similar EEG traces in Fmr1 KO mice as ones typically observed in FXS patients, making this experiment a highly valued translational test for model characterization and intervention studies.  

Experimental setup for auditory event-related potential (AERP) EEG recording

FIGURE 1. Experimental setup for auditory event-related potential (AERP) EEG recording. During an ERP recording session, multiple trials are provided with a 100 msec white noise stimulus (~70 dB), with 4-6 sec inter-trial interval. Trials with movement artifacts (deducted from XYZ activity) are excluded, generating a clean average AERP trace for the auditory cortex electrode. 

Take-home message

With InnoSer, your research can benefit from our translationally relevant models combined with behavioural readouts that better predict clinical trial outcomes. In addition to the novel AERP-EEG recording protocol, our in-house validated behavioural assays cover a wide range of key FXS clinical characteristics, including learning and memory, social interaction, repetitive behaviours, anxiety-like behaviours, and sensory processing.    


  1. Consorthium TD, Bakker CE, Verheij C, Willemsen R, van der Helm R, Oerlemans F, Vermey M, Bygrave A, Hoogeveen A, Oostra BA, Reyniers E. Fmr1 knockout mice: a model to study fragile X mental retardation. Cell. 1994 Jul 15;78(1):23-33. 
  2. Lee AW, Ventola P, Budimirovic D, Berry-Kravis E, Visootsak J. Clinical development of targeted fragile X syndrome treatments: an industry perspective. Brain sciences. 2018 Dec 5;8(12):214. 
  3. Lovelace JW, Ethell IM, Binder DK, Razak KA. Translation-relevant EEG phenotypes in a mouse model of Fragile X Syndrome. Neurobiology of disease. 2018 Jul 1;115:39-48. 
  4. Schuelert N, Dorner‐Ciossek C, Brendel M, Rosenbrock H. A comprehensive analysis of auditory event‐related potentials and network oscillations in an NMDA receptor antagonist mouse model using a novel wireless recording technology. Physiological Reports. 2018 Aug;6(16):e13782. 

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