Abstract
Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability. Many symptoms of FXS overlap with those in autism including repetitive behaviors, language delays, anxiety, social impairments and sensory processing deficits. Electroencephalogram (EEG) recordings from humans with FXS and an animal model, the Fmr1 knockout (KO) mouse, show remarkably similar phenotypes suggesting that EEG phenotypes can serve as biomarkers for developing treatments. This includes enhanced resting gamma band power and sound evoked total power, and reduced fidelity of temporal processing and habituation of responses to repeated sounds. Given the therapeutic potential of the antibiotic minocycline in humans with FXS and animal models, it is important to determine sensitivity and selectivity of EEG responses to minocycline. Therefore, in this study, we examined if a 10-day treatment of adult Fmr1 KO mice with minocycline (oral gavage, 30 mg/kg per day) would reduce EEG abnormalities. We tested if minocycline treatment has specific effects based on the EEG measurement type (e.g., resting versus sound-evoked) from the frontal and auditory cortex of the Fmr1 KO mice. We show increased resting EEG gamma power and reduced phase locking to time varying stimuli as well as the 40 Hz auditory steady state response in the Fmr1 KO mice in the pre-drug condition. Minocycline treatment increased gamma band phase locking in response to auditory stimuli, and reduced sound-evoked power of auditory event related potentials (ERP) in Fmr1 KO mice compared to vehicle treatment. Minocycline reduced resting EEG gamma power in Fmr1 KO mice, but this effect was similar to vehicle treatment. We also report frequency band-specific effects on EEG responses. Taken together, these data indicate that sound-evoked EEG responses may serve as more sensitive measures, compared to resting EEG measures, to isolate minocycline effects from placebo in humans with FXS. Given the use of minocycline and EEG recordings in a number of neurodegenerative and neurodevelopmental conditions, these findings may be more broadly applicable in translational neuroscience.
Highlights
Fragile X Syndrome (FXS) is a genetic cause of intellectual disability (Crawford et al, 2001) that results from a mutation in the Fragile X Mental Retardation 1 (Fmr1) gene and downregulation of Fragile X Mental Retardation Protein (FMRP) (Yu et al, 1991)
We report that minocycline treatment reduces sound evoked, but not resting state, EEG abnormalities in Fmr1 KO mice compared to vehicle treatment
The main goal of this study was to determine if 10 days of daily minocycline treatment, compared to vehicle, reversed resting state and sound-evoked EEG phenotypes in the auditory and frontal cortex (AC, FC) of adult Fmr1 KO mice
Summary
Fragile X Syndrome (FXS) is a genetic cause of intellectual disability (Crawford et al, 2001) that results from a mutation in the Fragile X Mental Retardation 1 (Fmr1) gene and downregulation of Fragile X Mental Retardation Protein (FMRP) (Yu et al, 1991). Abnormal sensory processing in humans with FXS includes hypersensitivity and reduced habituation to repeated sensory stimuli (Castrén et al, 2003; Schneider et al, 2013) These symptoms affect multiple sensory systems (Rais et al, 2018), are seen from early in development, and may lead to cognitive deficits and anxiety (Orefice et al, 2016). Ethridge et al (2016) studied age-matched control (mean age = 28.8 years) and patients with FXS (mean age = 28.5) and recorded ERPs in response to repetitions (2 Hz repetition rate) of the same tone (1000 Hz, 65 dB) They found that the N1 amplitude showed reduced habituation across repeated stimuli in humans with FXS. These correlations suggest clinical significance of EEG phenotypes in humans with FXS
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