Genetic reduction of MMP-9 in the Fmr1 KO mouse partially rescues prepulse inhibition of acoustic startle response

Kokash, Jamiela; Alderson, Erin; Reinhard, Sarah M.; Crawford, Cynthia A.; Binder, Devin K.; Ethell, Iryna M.; Razak, Khaleel A.

doi:10.1016/j.brainres.2019.05.029

Cited by 19 publications

(20 citation statements)

References 41 publications

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“…130,[134][135][136][137][138][139][140][141][142][143][144][145] Other studies reported unaltered, enhanced ASR, or reduced PPI. 134,138,139,142 Potential contributors to these discrepancies include, but are not limited to, the genetic background, 140,146 sex (147; but also see137), age, 145 and the sound level for triggering ASR. 140 Particularly, strainspecific differences have been reported in a variety of behavioral phenotypes following Fmr1 deletion 142 and it is known that different mouse strains exhibit varying degrees of ASR in wild-type mouse strains.…”

Section: Altered Asr and Ppimentioning

confidence: 99%

“…Interestingly, studies of Fmr1 knockout mice show mixed results, perhaps because of the very different hearing range of humans and mice. Many studies found reduced ASR to startle sounds at the level of 90‐120 dB, along with enhanced PPI, as compared to age‐matched wild‐type mice . Other studies reported unaltered, enhanced ASR, or reduced PPI .…”

Section: Audition‐associated Behavioral Changes In Fxsmentioning

confidence: 99%

“…Many studies found reduced ASR to startle sounds at the level of 90‐120 dB, along with enhanced PPI, as compared to age‐matched wild‐type mice . Other studies reported unaltered, enhanced ASR, or reduced PPI . Potential contributors to these discrepancies include, but are not limited to, the genetic background, sex (147; but also see137), age, and the sound level for triggering ASR .…”

Section: Audition‐associated Behavioral Changes In Fxsmentioning

confidence: 99%

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Mechanisms underlying auditory processing deficits in Fragile X syndrome

et al. 2020

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Autism spectrum disorders (ASD) are strongly associated with auditory hypersensitivity or hyperacusis (difficulty tolerating sounds). Fragile X syndrome (FXS), the most common monogenetic cause of ASD, has emerged as a powerful gateway for exploring underlying mechanisms of hyperacusis and auditory dysfunction in ASD. This review discusses examples of disruption of the auditory pathways in FXS at molecular, synaptic, and circuit levels in animal models as well as in FXS individuals. These examples highlight the involvement of multiple mechanisms, from aberrant synaptic development and ion channel deregulation of auditory brainstem circuits, to impaired neuronal plasticity and network hyperexcitability in the auditory cortex. Though a relatively new area of research, recent discoveries have increased interest in auditory dysfunction and mechanisms underlying hyperacusis in this disorder. This rapidly growing body of data has yielded novel research directions addressing critical questions regarding the timing and possible outcomes of human therapies for auditory dysfunction in ASD.

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Section: Altered Asr and Ppimentioning

confidence: 99%

Section: Audition‐associated Behavioral Changes In Fxsmentioning

confidence: 99%

Section: Audition‐associated Behavioral Changes In Fxsmentioning

confidence: 99%

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Mechanisms underlying auditory processing deficits in Fragile X syndrome

et al. 2020

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“…the Fmr1 KO mouse also shows auditory hypersensitivity, including enhanced cortical responses to sounds, increased propensity for AGS and abnormal sensorimotor gating (Chen and Toth, 2001;Frankland et al, 2004;Rotschafer and Razak, 2013;Wen et al, 2018;Kokash et al, 2019). Electroencephalographic (EEG) recordings demonstrate remarkably similar phenotypes in the Fmr1 KO mouse and humans with FXS (Castrén et al, 2003;Ethridge et al, 2017;Lovelace et al, 2016Lovelace et al, , 2018Schneider et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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

Binder

Ethell

Razak

2020

Journal of Neurophysiology

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Autism spectrum disorders (ASD) are commonly associated with sensory sensitivity issues, but the underlying mechanisms are unclear. This study presents novel evidence for neural correlates of auditory hypersensitivity in the developing inferior colliculus (IC) in the Fmr1 knockout (KO) mouse, a mouse model of Fragile X Syndrome (FXS), a leading genetic cause of ASD. Responses begin to show genotype differences between postnatal days 14 and 21, suggesting an early developmental treatment window.

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“…MMP-9 is an endopeptidase involved in activity-dependent modifications of the extracellular matrix ( Reinhard et al, 2015 ). MMP-9 is a target of FMRP-dependent translation regulation, and MMP-9 activity is upregulated in the auditory cortex ( Wen et al, 2018 ) and inferior colliculus ( Kokash et al, 2019 ) of Fmr1 KO mice. Genetic reduction of MMP-9 ameliorated correlates of auditory hypersensitivity in the Fmr1 KO mice including normalization of auditory ERP habituation ( Lovelace et al, 2016 ), pre-pulse inhibition of auditory startle ( Kokash et al, 2019 ) and calling rate of ultrasonic vocalizations ( Toledo et al, 2019 ).…”

Section: Introductionmentioning

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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Genetic reduction of MMP-9 in the Fmr1 KO mouse partially rescues prepulse inhibition of acoustic startle response

Cited by 19 publications

References 41 publications

Mechanisms underlying auditory processing deficits in Fragile X syndrome

Mechanisms underlying auditory processing deficits in Fragile X syndrome

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

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

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