Combined Treatment with Minocycline and an mGluR5 Antagonist Alters Resting EEG Spectral Power, but Not Sound-Evoked Responses, in a Mouse Model of Fragile X Syndrome

Abstract Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and autism-like behaviors. Glutamatergic mGluR5 receptors and matrix metalloproteinase-9 (MMP-9) are therapeutic targets to treat FXS, but clinical trials targeting each of these pathways have not been successful. Here, we tested if the electroencephalography (EEG) phenotypes associated with FXS are reversed with a novel combination of treatments affecting the two pathways. Fmr1 knockout (KO) mice were given 10 days of CTEP (mGluR5 antagonist) alone or in combination with minocycline (MMP-9 inhibitor). EEG was recorded during resting (no acoustic stimulation) and during sound presentations (to produce sound-evoked EEG) at 1 day and 10 days after the beginning of treatment administration to test acute effects and potential tachyphylaxis. In pre-treatment WT and KO mice comparisons, we replicated previously published Fmr1 KO mouse EEG phenotypes including elevated power in the resting gamma band, elevated single trial power, and reduced phase-locking to spectrotemporally dynamic auditory stimuli. We found that CTEP treatment alone did not show any benefit compared to vehicle in Fmr1 KO mice after either 1 or 10 days of treatment. CTEP + minocycline reduced resting gamma band power in the Fmr1 KO mice to a greater extent than vehicle at both treatment time points. There were no effects on sound-evoked responses. These data suggest that combined CTEP and minocycline treatment alters resting EEG measures while each treatment administered separately does not yield similar changes. High power in broadband gamma frequency correlates with irritability, stereotyped behaviors, and hyperactivity in FXS patients, suggesting a combination of drugs that reduce mGluR5 and MMP-9 activity may be beneficial in FXS.

• Publication year

  2025

• Venue

  ASN Neuro

• Publication date

  2025-10-16

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1080/17590914.2025.2564628PMID 41097999PMCID 12533955
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Clinically-probed mechanisms of action in Fragile-X Syndrome fail to normalize translational EEG phenotypes in Fmr1 knockout mice.

  2024cited by this paper
• Results from a Double-Blind, Randomized, Placebo-Controlled, Single-Dose, Crossover Trial of Lovastatin or Minocycline in Fragile X Syndrome

  2024cited by this paper
• 40 Hz Steady-State Response in Human Auditory Cortex Is Shaped by Gabaergic Neuronal Inhibition

  2024cited by this paper
• Phenotypic analysis of multielectrode array EEG biomarkers in developing and adult male Fmr1 KO mice.

  2024cited by this paper
• A novel combination treatment for fragile X syndrome predicted using computational methods

  2023cited by this paper
• Developmental delays in cortical auditory temporal processing in a mouse model of Fragile X syndrome

  2023cited by this paper
• Endogenous noise of neocortical neurons correlates with atypical sensory response variability in the Fmr1−/y mouse model of autism

  2023cited by this paper
• How dendritic spines shape is determined by MMP-9 activity in FXS.

  2023cited by this paper
• Combining Lovastatin and Minocycline for the Treatment of Fragile X Syndrome: Results From the LovaMiX Clinical Trial

  2022cited by this paper
• Improvement of sensory deficits in Fragile X mice by increasing cortical interneuron activity after the critical period

  2022cited by this paper
• Clinical significance of matrix metalloproteinase-9 in Fragile X Syndrome

  2022cited by this paper
• The PDE10A Inhibitor TAK-063 Reverses Sound-Evoked EEG Abnormalities in a Mouse Model of Fragile X Syndrome

  2021cited by this paper
• Role of matrix metalloproteinase-9 in neurodevelopmental deficits and experience-dependent plasticity in Xenopus laevis

  2021cited by this paper
• Gaboxadol in Fragile X Syndrome: A 12-Week Randomized, Double-Blind, Parallel-Group, Phase 2a Study

  2021cited by this paper
• Neural Correlates of Auditory Hypersensitivity in Fragile X Syndrome

  2021influential reference
• mGluR5 Negative Modulators for Fragile X: Treatment Resistance and Persistence

  2021cited by this paper
• Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial

  2021cited by this paper
• Neural Mechanisms Underlying Human Auditory Evoked Responses Revealed By Human Neocortical Neurosolver

  2021cited by this paper
• Sex differences in resting EEG power in Fragile X Syndrome.

  2021cited by this paper
• Increased aperiodic gamma power in young boys with Fragile X Syndrome is associated with better language ability

  2020cited by this paper
• Age- and movement-related modulation of cortical oscillations in a mouse model of presbycusis.

  2020cited by this paper
• Minocycline Treatment Reverses Sound Evoked EEG Abnormalities in a Mouse Model of Fragile X Syndrome

  2020influential reference
• Response to Placebo in Fragile X Syndrome Clinical Trials: An Initial Analysis

  2020cited by this paper
• Acute pharmacological inhibition of matrix metalloproteinase‐9 activity during development restores perineuronal net formation and normalizes auditory processing in Fmr1 KO mice

  2020cited by this paper
• Multielectrode array analysis of EEG biomarkers in a mouse model of Fragile X Syndrome.

  2020cited by this paper
• Human Neocortical Neurosolver (HNN), a new software tool for interpreting the cellular and network origin of human MEG/EEG data

  2020cited by this paper
• Effects of blocking mGluR5 on primate dorsolateral prefrontal cortical neuronal firing and working memory performance

  2020cited by this paper
• Genetic reduction of MMP-9 in the Fmr1 KO mouse partially rescues prepulse inhibition of acoustic startle response.

  2019cited by this paper
• Reduced auditory steady state responses in autism spectrum disorder

  2019cited by this paper
• Auditory EEG Biomarkers in Fragile X Syndrome: Clinical Relevance

  2019influential reference
• Human Neocortical Neurosolver (HNN): A new software tool for interpreting the cellular and network origin of human MEG/EEG data

  2019cited by this paper
• Reversal of ultrasonic vocalization deficits in a mouse model of Fragile X Syndrome with minocycline treatment or genetic reduction of MMP-9.

  2019cited by this paper
• Developmental Changes in EEG Phenotypes in a Mouse Model of Fragile X Syndrome.

  2019cited by this paper
• Reusable Multielectrode Array Technique for Electroencephalography in Awake Freely Moving Mice

  2018cited by this paper
• Syndrome

  2018cited by this paper
• Translation-relevant EEG phenotypes in a mouse model of Fragile X Syndrome.

  2018influential reference
• Genetic Reduction of Matrix Metalloproteinase-9 Promotes Formation of Perineuronal Nets Around Parvalbumin-Expressing Interneurons and Normalizes Auditory Cortex Responses in Developing Fmr1 Knock-Out Mice

  2018influential reference
• Neurotransmitter- and Release-Mode-Specific Modulation of Inhibitory Transmission by Group I Metabotropic Glutamate Receptors in Central Auditory Neurons of the Mouse

  2018cited by this paper
• Sensory Processing Phenotypes in Fragile X Syndrome

  2018cited by this paper
• Cortical gamma band synchronization through somatostatin interneurons

  2017cited by this paper
• A resting EEG study of neocortical hyperexcitability and altered functional connectivity in fragile X syndrome

  2017cited by this paper
• Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome

  2017cited by this paper
• Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome

  2017cited by this paper
• Chapter 9 – The mGluR Theory of Fragile X: From Mice to Men

  2017cited by this paper
• Distinct Inhibitory Circuits Orchestrate Cortical beta and gamma Band Oscillations.

  2017cited by this paper
• Transient ECM protease activity promotes synaptic plasticity

  2016cited by this paper
• Matrix metalloproteinase-9 deletion rescues auditory evoked potential habituation deficit in a mouse model of Fragile X Syndrome.

  2016influential reference
• Chronic Pharmacological mGluR5 Inhibition Prevents Cognitive Impairment and Reduces Pathogenesis in an Alzheimer Disease Mouse Model.

  2016cited by this paper
• A delicate balance: role of MMP-9 in brain development and pathophysiology of neurodevelopmental disorders

  2015cited by this paper
• Perineuronal net degradation in epilepsy

  2015cited by this paper
• Disruption of mGluR5 in parvalbumin-positive interneurons induces core features of neurodevelopmental disorders

  2015influential reference
• Matrix metalloproteinase-9 involvement in the structural plasticity of dendritic spines

  2014cited by this paper
• Metabotropic glutamate receptors in auditory processing.

  2014cited by this paper
• Parvalbumin Cell Ablation of NMDA-R1 Causes Increased Resting Network Excitability with Associated Social and Self-Care Deficits

  2014cited by this paper
• Pharmacogenetic Inhibition of eIF4E-Dependent Mmp9 mRNA Translation Reverses Fragile X Syndrome-like Phenotypes

  2014influential reference
• Genetic Removal of Matrix Metalloproteinase 9 Rescues the Symptoms of Fragile X Syndrome in a Mouse Model

  2014cited by this paper
• 2-Methyl-6-(phenylethynyl) pyridine (MPEP) reverses maze learning and PSD-95 deficits in Fmr1 knock-out mice

  2014cited by this paper
• The auditory steady-state response (ASSR): a translational biomarker for schizophrenia.

  2013cited by this paper
• Electrocortical changes associated with minocycline treatment in fragile X syndrome

  2013cited by this paper
• The Fragile X Mental Retardation Protein Regulates Matrix Metalloproteinase 9 mRNA at Synapses

  2013influential reference
• Long-lasting effects of minocycline on behavior in young but not adult Fragile X mice.

  2013cited by this paper
• Altered auditory processing in a mouse model of fragile X syndrome.

  2013cited by this paper
• High MMP‐9 activity levels in fragile X syndrome are lowered by minocycline

  2013cited by this paper
• Auditory and visual cortical activity during selective attention in fragile X syndrome: a cascade of processing deficiencies.

  2012cited by this paper
• Mechanisms of gamma oscillations.

  2012cited by this paper
• Minocycline treatment reverses ultrasonic vocalization production deficit in a mouse model of Fragile X Syndrome.

  2012cited by this paper
• Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice.

  2012influential reference
• The pathophysiology of fragile X (and what it teaches us about synapses).

  2012cited by this paper
• Learning and Memory Deficits Consequent to Reduction of the Fragile X Mental Retardation Protein Result from Metabotropic Glutamate Receptor-Mediated Inhibition of cAMP Signaling in Drosophila

  2012cited by this paper
• Event-related potential alterations in fragile X syndrome

  2012cited by this paper
• CTEP: A Novel, Potent, Long-Acting, and Orally Bioavailable Metabotropic Glutamate Receptor 5 Inhibitor

  2011cited by this paper
• Profiling cognition in fragile X syndrome: A psychophysiological and neuropsychological approach

  2011cited by this paper
• Fragile X Syndrome: The GABAergic System and Circuit Dysfunction

  2011cited by this paper
• Metabotropic glutamate receptors: physiology, pharmacology, and disease.

  2010cited by this paper
• Driving fast-spiking cells induces gamma rhythm and controls sensory responses

  2009cited by this paper
• Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model

  2008cited by this paper
• Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndrome

  2008cited by this paper
• Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice.

  2008cited by this paper
• Matrix metalloproteinases in brain development and remodeling: Synaptic functions and targets

  2007cited by this paper
• Correction of fragile X syndrome in mice.

  2007cited by this paper
• Nonparametric statistical testing of EEG- and MEG-data.

  2007cited by this paper
• Contribution of mGluR and Fmr1 functional pathways to neurite morphogenesis, craniofacial development and fragile X syndrome.

  2006cited by this paper
• Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP.

  2005cited by this paper
• Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome.

  2005cited by this paper
• Prolonged Epileptiform Discharges Induced by Altered Group I Metabotropic Glutamate Receptor-Mediated Synaptic Responses in Hippocampal Slices of a Fragile X Mouse Model

  2005cited by this paper
• Overexpression of type-1 adenylyl cyclase in mouse forebrain enhances recognition memory and LTP

  2004cited by this paper
• Human temporal auditory acuity as assessed by envelope following responses.

  2004cited by this paper
• What the rodent prefrontal cortex can teach us about attention-deficit/hyperactivity disorder: the critical role of early developmental events on prefrontal function.

  2003cited by this paper
• Altered synaptic plasticity in a mouse model of fragile X mental retardation

  2002influential reference
• FMR1 and the fragile X syndrome: Human genome epidemiology review

  2001cited by this paper
• Understanding the molecular basis of fragile X syndrome.

  2000cited by this paper
• Fine-Tuning an Auditory Synapse for Speed and Fidelity: Developmental Changes in Presynaptic Waveform, EPSC Kinetics, and Synaptic Plasticity

  2000cited by this paper
• Differential Presynaptic Localization of Metabotropic Glutamate Receptor Subtypes in the Rat Hippocampus

  1997cited by this paper
• Differential plasma membrane distribution of metabotropic glutamate receptors mGluR1 alpha, mGluR2 and mGluR5, relative to neurotransmitter release sites.

  1997cited by this paper
• Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain

  1995cited by this paper
• Reduced Cyclic AMP Production in Fragile X Syndrome: Cytogenetic and Molecular Correlations

  1995cited by this paper
• Direct patch recording from identified presynaptic terminals mediating glutamatergic EPSCs in the rat CNS, in vitro.

  1994cited by this paper
• Advances in molecular analysis of fragile X syndrome.

  1994cited by this paper
• Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome

  1991cited by this paper
• Fragile X genotype characterized by an unstable region of DNA

  1991cited by this paper

• No citing papers are available for this paper.