Reduced habituation of auditory evoked potentials indicate cortical hyper-excitability in Fragile X Syndrome

Ethridge, Lauren E.; White, Steven J.; Mosconi, Matthew W.; Wang, J.; Byerly, Matthew J.; Sweeney, John A.

doi:10.1038/tp.2016.48

Cited by 152 publications

(204 citation statements)

References 43 publications

(68 reference statements)

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“…Poorly organized inhibitory drive onto pyramidal cells in auditory cortex from fast-spiking interneurons that control gamma synchronization could account for the pattern we observed of increased gamma power, suggesting increased high-frequency firing of excitatory pyramidal neurons (noise) but with less coherent organization (phase-locking) in response to sensory stimulation. This pattern of alterations may contribute to previously reported decreases in transient gamma phase-locking [13]. Given the similar network dynamics observed in Fmr1 rodent models [5, 7, 14, 44], findings reported here may not only extend mouse model concepts to FXS patients, but suggest that neurophysiological measures may be useful for tracking this local circuit deficit in both mouse models and patients to foster direct translational drug development for this neurodevelopmental disorder.…”

Section: Discussionsupporting

confidence: 78%

Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome

et al. 2017

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BackgroundStudies in the fmr1 KO mouse demonstrate hyper-excitability and increased high-frequency neuronal activity in sensory cortex. These abnormalities may contribute to prominent and distressing sensory hypersensitivities in patients with fragile X syndrome (FXS). The current study investigated functional properties of auditory cortex using a sensory entrainment task in FXS.MethodsEEG recordings were obtained from 17 adolescents and adults with FXS and 17 age- and sex-matched healthy controls. Participants heard an auditory chirp stimulus generated using a 1000-Hz tone that was amplitude modulated by a sinusoid linearly increasing in frequency from 0–100 Hz over 2 s.ResultsSingle trial time-frequency analyses revealed decreased gamma band phase-locking to the chirp stimulus in FXS, which was strongly coupled with broadband increases in gamma power. Abnormalities in gamma phase-locking and power were also associated with theta-gamma amplitude-amplitude coupling during the pre-stimulus period and with parent reports of heightened sensory sensitivities and social communication deficits.ConclusionsThis represents the first demonstration of neural entrainment alterations in FXS patients and suggests that fast-spiking interneurons regulating synchronous high-frequency neural activity have reduced functionality. This reduced ability to synchronize high-frequency neural activity was related to the total power of background gamma band activity. These observations extend findings from fmr1 KO models of FXS, characterize a core pathophysiological aspect of FXS, and may provide a translational biomarker strategy for evaluating promising therapeutics.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-017-0140-1) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 78%

Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome

et al. 2017

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“…It is observed in humans with FXS (Ethridge et al 2016) and ASD (Orekhova et al 2007; Wang et al 2013). It is also seen in Fmr1 KO mice in vivo (in this study) and in vitro in thalamocortical slices from Fmr1 KO mice (Gibson et al 2008).…”

Section: Discussionmentioning

confidence: 99%

GABA-B Agonist Baclofen Normalizes Auditory-Evoked Neural Oscillations and Behavioral Deficits in theFmr1Knockout Mouse Model of Fragile X Syndrome

Sinclair

Featherstone

Naschek

et al. 2017

eNeuro

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Fragile X syndrome is a genetic condition resulting from FMR1 gene mutation that leads to intellectual disability, autism-like symptoms, and sensory hypersensitivity. Arbaclofen, a GABA-B agonist, has shown efficacy in some individuals with FXS but has become unavailable after unsuccessful clinical trials, prompting interest in publicly available, racemic baclofen. The present study investigated whether racemic baclofen can remediate abnormalities of neural circuit function, sensory processing, and behavior in Fmr1 knockout mice, a rodent model of fragile X syndrome. Fmr1 knockout mice showed increased baseline and auditory-evoked high-frequency gamma (30–80 Hz) power relative to C57BL/6 controls, as measured by electroencephalography. These deficits were accompanied by decreased T maze spontaneous alternation, decreased social interactions, and increased open field center time, suggestive of diminished working memory, sociability, and anxiety-like behavior, respectively. Abnormal auditory-evoked gamma oscillations, working memory, and anxiety-related behavior were normalized by treatment with baclofen, but impaired sociability was not. Improvements in working memory were evident predominantly in mice whose auditory-evoked gamma oscillations were dampened by baclofen. These findings suggest that racemic baclofen may be useful for targeting sensory and cognitive disturbances in fragile X syndrome.

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“…Remarkably, weak habituation is a particularly common feature of autism spectrum disorders (ASD) that is also observed in schizophrenia (31,(82)(83)(84)(85). Weak habituation could also result in several downstream cognitive changes observed in autism and in schizophrenia, including altered sensory gating, stimulus hypersensitivity, and reduced ability to cope in complex environments, where multiple signals may appear salient and compete for attention (10,31,82,85,86). It is also conceivable that additional features of autism, such as sticky attention, wherein familiar stimuli remain engaging for unusually long periods of time while novel stimuli seem challenging, could arise from weak habituation and hypersensitivity to novel stimuli (85)(86)(87)).…”

Section: Implications For Ei Disruption In Clinical Conditionsmentioning

confidence: 99%

Inhibitory engrams in perception and memory

Barron

Vogels

Behrens

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

135

126

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Nervous systems use excitatory cell assemblies to encode and represent sensory percepts. Similarly, synaptically connected cell assemblies or "engrams" are thought to represent memories of past experience. Multiple lines of recent evidence indicate that brain systems create and use inhibitory replicas of excitatory representations for important cognitive functions. Such matched "inhibitory engrams" can form through homeostatic potentiation of inhibition onto postsynaptic cells that show increased levels of excitation. Inhibitory engrams can reduce behavioral responses to familiar stimuli, thereby resulting in behavioral habituation. In addition, by preventing inappropriate activation of excitatory memory engrams, inhibitory engrams can make memories quiescent, stored in a latent form that is available for contextrelevant activation. In neural networks with balanced excitatory and inhibitory engrams, the release of innate responses and recall of associative memories can occur through focused disinhibition. Understanding mechanisms that regulate the formation and expression of inhibitory engrams in vivo may help not only to explain key features of cognition but also to provide insight into transdiagnostic traits associated with psychiatric conditions such as autism, schizophrenia, and posttraumatic stress disorder.Percepts are thought to be represented in the brain by excitatory activity in groups of neurons, described as cell assemblies (1). Memories may similarly be represented by excitatory connections across different cell assemblies, which form when experiences trigger coordinated activity. Several recent studies indicate that the storage and reactivation of these excitatory "engrams" (2), respectively, may be accompanied by creation and modulation of matched inhibitory engrams. Here, we propose that inhibitory engrams, also termed "negative images" or "inhibitory representations," explain two fundamental features of animal and human psychology: first, behavioral habituation, which allows organisms to ignore familiar, frequently encountered percepts or stimuli, and, second, latent memory, wherein the brain stores tens of thousands of memories in a silent or latent state until recall is required. Such inhibitory engrams can be constructed in neural networks through simple, evolutionarily primitive, synaptic and cellular mechanisms, which are recognized to be involved in the phenomenon of excitatory-inhibitory (EI) balance observed across the brain.Neurons and neural circuits normally operate within a preset range of activity. Outside this range, altered levels of neuronal spiking trigger a variety of homeostatic mechanisms ranging from compensatory ion channel expression to local synaptic scaling (3, 4). These homeostatic mechanisms ensure that the activity parameters of a neuron operate around a set point such that the spiking rates remain stable and a balance of depolarizing and hyperpolarizing currents is maintained. As a consequence, excitation and inhibition are both locally and globally balanced, despite...

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Reduced habituation of auditory evoked potentials indicate cortical hyper-excitability in Fragile X Syndrome

Cited by 152 publications

References 43 publications

Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome

Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome

GABA-B Agonist Baclofen Normalizes Auditory-Evoked Neural Oscillations and Behavioral Deficits in theFmr1Knockout Mouse Model of Fragile X Syndrome

Inhibitory engrams in perception and memory

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