Local cortical circuit correlates of altered EEG in the mouse model of Fragile X syndrome

Goswami, Sayantani; Cavalier, Sheridan; Sridhar, Vinay; Huber, Kimberly M.; Gibson, Jay R.

doi:10.1016/j.nbd.2019.01.002

Cited by 39 publications

(37 citation statements)

References 46 publications

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“…Increased amplitude and reduced habituation of auditory ERPs are also seen in the Fmr1 KO mice ( Lovelace et al, 2016 ; Sinclair et al, 2017b ; Wen et al, 2019 ; Kulinich et al, 2020 ). These data are consistent with in vivo cortical single cell recordings that show auditory hyper-responsiveness and broader frequency tuning curves ( Rotschafer and Razak, 2013 ; Wen et al, 2018 ) and in vitro cortical slice preparations that show enhanced gamma band power in auditory cortex and synchrony across cortical layers ( Goswami et al, 2019 ). Sinclair et al (2017a) showed that racemic baclofen, an agonist of GABA-b receptors, reduced abnormalities in sound evoked gamma oscillations in the ERP recorded from Fmr1 KO mice.…”

Section: Introductionsupporting

confidence: 86%

“…The gamma fluctuations consisted of both fast depolarization and GABAergic inhibition. Given the broader tuning curves of cortical neurons in the Fmr1 KO mice, and increased synchrony across neurons (Goswami et al, 2019), the transient neural assemblies formed in the 150-400 msec window after stimulus onset may incorporate the activity of a larger number of neurons with overlapping tuning. This would produce the observed increase in induced gamma power.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Introductionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…To our knowledge, this is the first study to show abnormal task-related high-frequency activity time-locked to behaviour in patients with FXS. An imbalance of excitation, inhibition or exaggerated excitability of pyramidal neurons, is believed to underlie atypical gamma oscillations in FXS based on preclinical observations ( Gibson et al , 2008 ; Goswami et al , 2019 ), suggesting that current observations of elevated pre-speech gamma also may arise from a similar fundamental mechanism. This could help account for the lack of association between high-frequency activity and alpha/theta band fronto-temporal coherence in FXS, a relationship noted in our TDC sample.…”

Section: Discussionmentioning

confidence: 83%

“…Our findings of clinically relevant fronto-temporal connectivity alterations and elevated gamma power before speech onset might be best understood in the context of aberrant neural synchronization of auditory cortical responses to tones and increased intrinsic high-frequency activity in patients with FXS and in FMR1 KO mice in vivo and in vitro ( Hou et al , 2006 ; Osterweil et al , 2010 ; Choi et al , 2011 ; Ethridge et al , 2016 , 2017 ; Wang et al , 2017 ; Lovelace et al , 2018 ; Goswami et al , 2019 ). Auditory processing alterations may contribute to the atypical development of speech and language skills in FXS.…”

Section: Discussionmentioning

confidence: 89%

A neurophysiological model of speech production deficits in fragile X syndrome

Schmitt

Wang

Pedapati

et al. 2019

Brain Communications

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Fragile X syndrome is the most common inherited intellectual disability and monogenic cause of autism spectrum disorder. Expressive language deficits, especially in speech production, are nearly ubiquitous among individuals with fragile X, but understanding of the neurological bases for these deficits remains limited. Speech production depends on feedforward control and the synchronization of neural oscillations between speech-related areas of frontal cortex and auditory areas of temporal cortex. Interaction in this circuitry allows the corollary discharge of intended speech generated from an efference copy of speech commands to be compared against actual speech sounds, which is critical for making adaptive adjustments to optimize future speech. We aimed to determine whether alterations in coherence between frontal and temporal cortices prior to speech production are present in individuals with fragile X and whether they relate to expressive language dysfunction. Twenty-one participants with full-mutation fragile X syndrome (aged 7–55 years, eight females) and 20 healthy controls (matched on age and sex) completed a talk/listen paradigm during high-density EEG recordings. During the talk task, participants repeated pronounced short vocalizations of ‘Ah’ every 1–2 s for a total of 180 s. During the listen task, participants passively listened to their recordings from the talk task. We compared pre-speech event-related potential activity, N1 suppression to speech sounds, single trial gamma power and fronto-temporal coherence between groups during these tasks and examined their relation to performance during a naturalistic language task. Prior to speech production, fragile X participants showed reduced pre-speech negativity, reduced fronto-temporal connectivity and greater frontal gamma power compared to controls. N1 suppression during self-generated speech did not differ between groups. Reduced pre-speech activity and increased frontal gamma power prior to speech production were related to less intelligible speech as well as broader social communication deficits in fragile X syndrome. Our findings indicate that coordinated pre-speech activity between frontal and temporal cortices is disrupted in individuals with fragile X in a clinically relevant way and represents a mechanism contributing to prominent speech production problems in the disorder.

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“…Fmr1 deletion in cortical excitatory neurons and glial cells are neither sufficient nor necessary for recapitulating the AGS phenotype Sensory cortices in both Fmr1 KO mice and FXS patients have been reported to have enhanced sensory responses (Rotschafer and Razak, 2013;Zhang et al, 2014a), and sensory neocortical circuits are hyperexcitable, as measured in acute brain slices (Hays et al, 2011;Goswami et al, 2019). Therefore, it is possible that Fmr1 deletion in cortical structures results in enhanced responses in the cortex, which in turn, cause AGSs.…”

Section: Resultsmentioning

confidence: 99%

Audiogenic Seizures in theFmr1Knock-Out Mouse Are Induced byFmr1Deletion in Subcortical, VGlut2-Expressing Excitatory Neurons and Require Deletion in the Inferior Colliculus

Gonzalez¹,

Tomasek²,

Hays³

et al. 2019

J. Neurosci.

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Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading monogenetic cause of autism. One symptom of FXS and autism is sensory hypersensitivity (also called sensory over-responsivity). Perhaps related to this, the audiogenic seizure (AGS) is arguably the most robust behavioral phenotype in the FXS mouse model-the Fmr1 knockout (KO) mouse. Therefore, the AGS may be considered a mouse model of sensory hypersensitivity. Hyperactive circuits are hypothesized to underlie dysfunction in a number of brain regions in patients with FXS and Fmr1 KO mice, and the AGS may be a result of this. But the specific cell types and brain regions underlying AGSs in the Fmr1 KO are unknown. We used conditional deletion or expression of Fmr1 in different cell populations to determine whether Fmr1 deletion in those cells was sufficient or necessary, respectively, for the AGS phenotype in males. Our data indicate that Fmr1 deletion in glutamatergic neurons that express vesicular glutamate transporter 2 (VGlut2) and are located in subcortical brain regions is sufficient and necessary to cause AGSs. Furthermore, the deletion of Fmr1 in glutamatergic neurons of the inferior colliculus is necessary for AGSs. When we demonstrate necessity, we show that Fmr1 expression in either the larger population of VGlut2-expressing glutamatergic neurons or the smaller population of inferior collicular glutamatergic neurons-in an otherwise Fmr1 KO mouse-eliminates AGSs. Therefore, targeting these neuronal populations in FXS and autism may be part of a therapeutic strategy to alleviate sensory hypersensitivity.

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Local cortical circuit correlates of altered EEG in the mouse model of Fragile X syndrome

Cited by 39 publications

References 46 publications

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

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

A neurophysiological model of speech production deficits in fragile X syndrome

Audiogenic Seizures in theFmr1Knock-Out Mouse Are Induced byFmr1Deletion in Subcortical, VGlut2-Expressing Excitatory Neurons and Require Deletion in the Inferior Colliculus

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