Minocycline Treatment Reverses Sound Evoked EEG Abnormalities in a Mouse Model of Fragile X Syndrome

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.

A sound-driven cortical phase-locking change in the Fmr1 KO mouse requires Fmr1 deletion in a subpopulation of brainstem neurons

“…Based on previous publications ( Fig. 5A , D in ( Lovelace et al, 2020b )) and our data here, the other clusters most likely represent either third harmonics of beta- and gamma-related signals (above the ROI) or type I error (below the ROI). Our observation of decreased PLF at specific frequency bands in the Fmr1 KO confirm previous studies ( Lovelace et al, 2018 ; Jonak et al, 2020 ).…”

“…We refer to this as the single trial non-PL power, and it includes both “phase-locked” and “non-phase-locked” components relative to the chirp. Previous studies observed increased non-PL power in gamma frequency bands in Fmr1 KO mice ( Lovelace et al, 2018 ; Jonak et al, 2020 ; Lovelace et al, 2020b ) and have shown that it is due to deletion in the cortex ( Lovelace et al, 2020a ; Rais et al, 2021 ). Therefore, we hypothesized that reinstatement of Fmr1 in the Ntsr1 -marked neurons would not rescue this phenotype.…”

Auditory Dysfunction in Animal Models of Autism Spectrum Disorder

“…Furthermore, MMP-9 upregulation likely hinders the formation of perineuronal nets (PNNs) around parvalbumin-expressing (PV + ) cortical interneurons (GABAergic neurons), leading to reduced cortical network inhibition and E/I imbalance in the AC ( Wen et al, 2018 ). Genetic or pharmacological strategies for reducing MMP-9 levels seem to rescue the following phenotypes: (1) audiogenic seizure susceptibility, (2) AC activity (spontaneous and evoked), (3) auditory ERP habituation, (4) formation of PNNs around PV + cells, (5) anxiety-like and hyperactive behaviors, (6) ASR ( Gkogkas et al, 2014 ; Lovelace et al, 2016 , 2020a ; Wen et al, 2018 ; Kokash et al, 2019 ; Pirbhoy et al, 2020 ). Enhancement of endocannabinoid production (2-arachidonoyl-sn-glycerol) seems to ameliorate synchrony in the cortical response to auditory stimuli, and rescue anxiety-like and hyperactive behaviors ( Pirbhoy et al, 2021 ).…”

Auditory processing in rodent models of autism: a systematic review

“…Again, this strongly matches the divergent endophenotypes of FXS and iASD in humans. ITC of gamma activity is decreased in the auditory and frontal cortices of many ASD models [ 20 , 42 , 43 , 48 , 55 , 57 , 68 , 101 , 102 ]. Fewer studies found increased or unchanged gamma ITC, and most of these were in C57BL/6 mice over 3 months old [ 49 , 64 , 106 ].…”