Reversal of ultrasonic vocalization deficits in a mouse model of Fragile X Syndrome with minocycline treatment or genetic reduction of MMP-9

Toledo, Maximiliano A.; Wen, Teresa H.; Binder, Devin K.; Ethell, Iryna M.; Razak, Khaleel A.

doi:10.1016/j.bbr.2019.112068

Cited by 26 publications

(22 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The minocycline dose was chosen based on Bilousova et al (2009), who showed improvement in spine maturation and performance on behavioral tests in the Fmr1 KO mice. Dansie et al (2013) and Toledo et al (2019) used the same dose and found improvements in hyperactivity and ultrasonic vocalization phenotypes in the Fmr1 KO mice.…”

Section: Micementioning

confidence: 95%

“…Minocycline is a tetracycline antibiotic with multiple targets of action that include inflammation, apoptosis and microglial clearance. Minocycline also reduces MMP-9 levels (Dziembowska et al, 2013), and this effect may be associated with beneficial effects of minocycline treatment on neurobehavioral symptoms in multiple studies of animal models (Bilousova et al, 2009;Siller and Broadie, 2011;Rotschafer et al, 2012;Dansie et al, 2013;Toledo et al, 2019). These improvements include improvements in anxiety-like behavioral outcomes, ultrasonic vocalizations, pre-pulse inhibition of startle, dendritic spine density measurements and audiogenic seizures.…”

Section: Introductionmentioning

confidence: 98%

“…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 ). Single cell hyper-responsiveness and abnormal development of parvalbumin (PV) expressing inhibitory neurons in the auditory cortex of Fmr1 KO mice were also reversed by genetic reduction of MMP-9 in Fmr1 KO mice ( Wen et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Micementioning

confidence: 95%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…They found that minocycline reversed ultrasonic vocalization deficits through attenuation of MMP-9 levels, even when treated past the early developmental period. 20 Minocycline has also been shown to be beneficial in studies involving patients with FXS. Leigh and colleagues (2013) published a randomized doubleblind, placebo-controlled crossover trial of minocycline in children and adolescents with FXS.…”

Section: Minocyclinementioning

confidence: 99%

Fragile X Syndrome and Targeted Treatments

Tassanakijpanich

Cabal-Herrera²,

Salcedo-Arellano

et al. 2020

J. Biomed. Transl. Res.

View full text Add to dashboard Cite

Many targeted treatment studies have been carried out in individuals with Fragile X Syndrome (FXS) guided by animal studies from the Fragile X Mental Retardation 1 (FMR1) knock out (KO) mice and the fragile X Drosophila studies. Here we review the many medications that have been studied in patients with FXS and some of these medications are available for clinical use by wise clinicians. Other medications are not currently available by prescription because they are not approved by the FDA. No medication has received specific approval for treatment of FXS, although some have shown benefit from clinical studies. There is much to be done in the treatment of those with FXS and this report describes those pharmacological treatments that target the neurobiological mechanisms that are dysregulated by the lack of the Fragile X Protein (FMRP) in those with FXS.

show abstract

“…The main symptoms of FXS patients include cognitive disability, hyperactivity, and autism-related behavior 1,2 . Based on the pathological and mechanistic studies with animal models of FXS, strategies targeting specific molecular and cellular alterations have shown notable therapeutic efficacy in preclinical studies [3][4][5][6][7] . Nevertheless, efficacious medication is not available yet.…”

Section: Introductionmentioning

confidence: 99%

Vorinostat corrects cognitive and non-cognitive symptoms in a mouse model of fragile X syndrome

Ding

et al. 2020

Preprint

View full text Add to dashboard Cite

Fragile X syndrome (FXS) is caused by mutations in the FMR1 (fragile X mental retardation 1) gene. It is a significant form of heritable intellectual disability with comorbidity of other symptoms such as autism. Due to the lack of efficacious medication, repurposing the existing FDA-approved drugs may offer an opportunity to advance clinical intervention for FXS. Analysis of the whole-genome transcription signatures predicts new therapeutic action of vorinostat to correct pathological alterations associated with FXS. We further find that the administration of vorinostat restores object location memory and passive avoidance memory in the Fmr1 knockout (KO) mice. For the non-cognitive behavioral symptoms, vorinostat corrects the autism-associated alterations, including repetitive behavior and social interaction deficits. In the open field test, vorinostat dampens hyperactivity in the center area of the arena. Surprisingly, vorinostat does not affect the abnormally elevated protein synthesis in Fmr1 KO neurons, suggesting different outcomes from correcting behavioral symptoms and specific aspects of cellular pathology. Our data reveal the therapeutic effects of the FDA-approved drug vorinostat in a mouse model of FXS and advocate efficacy testing with human patients.

show abstract

Reversal of ultrasonic vocalization deficits in a mouse model of Fragile X Syndrome with minocycline treatment or genetic reduction of MMP-9

Cited by 26 publications

References 49 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

Fragile X Syndrome and Targeted Treatments

Vorinostat corrects cognitive and non-cognitive symptoms in a mouse model of fragile X syndrome

Contact Info

Product

Resources

About