Abnormal development of auditory responses in the inferior colliculus of a mouse model of Fragile X Syndrome

Binder, Devin K.; Ethell, Iryna M.; Razak, Khaleel A.

doi:10.1152/jn.00706.2019

Cited by 19 publications

(34 citation statements)

References 87 publications

(78 reference statements)

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“…Early childhood sensory processing abnormalities may lead to increased anxiety and delayed language development. In the mouse model of FXS, we have identified four neural correlates of auditory hypersensitivity: increased single neuron responses to sounds ( Rotschafer and Razak, 2013 ; Wen et al, 2019 ; Nguyen et al, 2020 ), more neurons activated by a single sound ( Rotschafer and Razak, 2013 ; Nguyen et al, 2020 ), reduced habituation of cortical responses to repeated sounds ( Lovelace et al, 2016 ) and abnormal synchrony of sound driven responses ( Lovelace et al, 2018 , 2019 ; Wen et al, 2019 ). Either genetic reduction of MMP-9 ( Lovelace et al, 2016 ; Wen et al, 2018 ) or reduction of MMP-9 with a specific inhibitor ( Pirbhoy et al, 2020 ) or with the FDA-approved minocycline normalized these abnormal responses (present study).…”

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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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: 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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“…Besides auditory cortex, FMRP expression is detected across the entire auditory neuraxis, with the possible exception of the cochlea (68)(69)(70). While the preponderance of studies in both humans and animal models have focused on the cortex, both subcortical site abnormalities and/or local cortical processing abnormalities may contribute to the phenotypes recorded in the cortex (70)(71)(72)(73). Indeed, both the brainstem and midbrain auditory nuclei show abnormal synaptic markers and electrophysiological responses.…”

Section: Disentangling Cortical Vs Subcortical Contributions To Auditory Hypersensitivitymentioning

confidence: 99%

“…Indeed, both the brainstem and midbrain auditory nuclei show abnormal synaptic markers and electrophysiological responses. The inferior colliculus shows broader frequency tuning curves, and enhanced responses to tones and amplitude modulated sounds (73). As in the cortex, these abnormalities develop between P14 and P21, a time window The table lists the major EEG findings in rodents and humans that could be used as EEG correlates of sensory hypersensitivity.…”

Section: Disentangling Cortical Vs Subcortical Contributions To Auditory Hypersensitivitymentioning

confidence: 99%

Neural Correlates of Auditory Hypersensitivity in Fragile X Syndrome

2021

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The mechanisms underlying the common association between autism spectrum disorders (ASD) and sensory processing disorders (SPD) are unclear, and treatment options to reduce atypical sensory processing are limited. Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and ASD behaviors. As in most children with ASD, atypical sensory processing is a common symptom in FXS, frequently manifesting as sensory hypersensitivity. Auditory hypersensitivity is a highly debilitating condition in FXS that may lead to language delays, social anxiety and ritualized repetitive behaviors. Animal models of FXS, including Fmr1 knock out (KO) mouse, also show auditory hypersensitivity, providing a translation relevant platform to study underlying pathophysiological mechanisms. The focus of this review is to summarize recent studies in the Fmr1 KO mouse that identified neural correlates of auditory hypersensitivity. We review results of electroencephalography (EEG) recordings in the Fmr1 KO mice and highlight EEG phenotypes that are remarkably similar to EEG findings in humans with FXS. The EEG phenotypes associated with the loss of FMRP include enhanced resting EEG gamma band power, reduced cross frequency coupling, reduced sound-evoked synchrony of neural responses at gamma band frequencies, increased event-related potential amplitudes, reduced habituation of neural responses and increased non-phase locked power. In addition, we highlight the postnatal period when the EEG phenotypes develop and show a strong association of the phenotypes with enhanced matrix-metalloproteinase-9 (MMP-9) activity, abnormal development of parvalbumin (PV)-expressing inhibitory interneurons and reduced formation of specialized extracellular matrix structures called perineuronal nets (PNNs). Finally, we discuss how dysfunctions of inhibitory PV interneurons may contribute to cortical hyperexcitability and EEG abnormalities observed in FXS. Taken together, the studies reviewed here indicate that EEG recordings can be utilized in both pre-clinical studies and clinical trials, while at the same time, used to identify cellular and circuit mechanisms of dysfunction in FXS. New therapeutic approaches that reduce MMP-9 activity and restore functions of PV interneurons may succeed in reducing FXS sensory symptoms. Future studies should examine long-lasting benefits of developmental vs. adult interventions on sensory phenotypes.

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“…Some studies have shown involvement of the inferior colliculi (e.g., Baldwin et al, 2016) among other brainstem structures such as inferior olives, corpus callosum, and cerebellum (Ritvo et al, 1986;Courchesne, 1997;Piven et al, 1997;Bailey et al, 1998;Kemper and Bauman, 1998) and links to mitochondrial dysfunction and disturbed brain energy metabolism (Lombard, 1998;Chauhan and Chauhan, 2006;Palmieri and Persico, 2010;Shoffner et al, 2010;Chauhan et al, 2011;Anitha et al, 2013;Siddiqui et al, 2016). In animal models, the genetic disorder Fragile X Syndrome likewise shows evidence for inferior colliculus involvement (Gonzalez et al, 2019;Kokash et al, 2019;Nguyen et al, 2020). Asphyxia at birth in humans (Schneider et al, 1975;Leech and Alvord, 1977;Roland et al, 1988) and in monkeys (Windle, 1969;Myers, 1972) results in disproportionate injury to thalamus and brainstem nuclei, particularly the inferior colliculi.…”

Section: Other Diseases Involving the Inferior Colliculimentioning

confidence: 99%

The Inferior Colliculus in Alcoholism and Beyond

Bordia

Zahr

2020

Front. Syst. Neurosci.

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Post-mortem neuropathological and in vivo neuroimaging methods have demonstrated the vulnerability of the inferior colliculus to the sequelae of thiamine deficiency as occurs in Wernicke-Korsakoff Syndrome (WKS). A rich literature in animal models ranging from mice to monkeys—including our neuroimaging studies in rats—has shown involvement of the inferior colliculi in the neural response to thiamine depletion, frequently accomplished with pyrithiamine, an inhibitor of thiamine metabolism. In uncomplicated alcoholism (i.e., absent diagnosable neurological concomitants), the literature citing involvement of the inferior colliculus is scarce, has nearly all been accomplished in preclinical models, and is predominately discussed in the context of ethanol withdrawal. Our recent work using novel, voxel-based analysis of structural Magnetic Resonance Imaging (MRI) has demonstrated significant, persistent shrinkage of the inferior colliculus using acute and chronic ethanol exposure paradigms in two strains of rats. We speculate that these consistent findings should be considered from the perspective of the inferior colliculi having a relatively high CNS metabolic rate. As such, they are especially vulnerable to hypoxic injury and may be provide a common anatomical link among a variety of disparate insults. An argument will be made that the inferior colliculi have functions, possibly related to auditory gating, necessary for awareness of the external environment. Multimodal imaging including diffusion methods to provide more accurate in vivo visualization and quantification of the inferior colliculi may clarify the roles of brain stem nuclei such as the inferior colliculi in alcoholism and other neuropathologies marked by altered metabolism.

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Abnormal development of auditory responses in the inferior colliculus of a mouse model of Fragile X Syndrome

Cited by 19 publications

References 87 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

Neural Correlates of Auditory Hypersensitivity in Fragile X Syndrome

The Inferior Colliculus in Alcoholism and Beyond

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