Chronic Pharmacological mGlu5 Inhibition Corrects Fragile X in Adult Mice
Open accessAbstract
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, but a crucial unanswered question is whether pharmacological mGlu5 inhibition is able to reverse an already established FXS phenotype in mammals. Here we have used the novel, potent, and selective mGlu5 inhibitor CTEP to address this issue in the Fmr1 knockout mouse. Acute CTEP treatment corrects elevated hippocampal long-term depression, protein synthesis, and audiogenic seizures. Chronic treatment that inhibits mGlu5 within a receptor occupancy range of 81% ± 4% rescues cognitive deficits, auditory hypersensitivity, aberrant dendritic spine density, overactive ERK and mTOR signaling, and partially corrects macroorchidism. This study shows that a comprehensive phenotype correction in FXS is possible with pharmacological intervention starting in young adulthood, after development of the phenotype. It is of great interest how these findings may translate into ongoing clinical research testing mGlu5 inhibitors in FXS patients.
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In a Fragile X mouse model, chronic administration of the mGluR5 negative allosteric modulator CTEP after adolescence reverses inhibitory avoidance deficits.
“In a mouse model of Fragile X Syndrome, IA deficits are reversed via chronic post-adolescent administration of the mGluR5 negative allosteric modulator (NAM) CTEP [97].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [97]
Chronic treatments with CTEP restored cognitive functions, ameliorated auditory hypersensitivity, aberrant dendritic spine density and overactive ERK and mTOR signaling, and partially corrected macroorchidism in male mouse models of fragile X syndrome.
“Chronic treatments with CTEP, a high affinity, longacting and orally bioavailable mGluR inhibitor, restored cognitive functions, ameliorated auditory hypersensitivity, aberrant dendritic spine density and overactive extracellular signal-regulated kinase (ERK) and mTOR signaling, and partially corrected the macroorchidism observed in male mouse models of fragile X syndrome 68 .”
From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [68]
Preclinical studies have primarily focused on mGluR5 signaling as potential targets for treatment in adult mice.
“Preclinical studies have primarily focused on mGluR5 signaling as potential targets for treatment in adult mice 99,110-113 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [111]
Pharmacological mGluR5 antagonists rescue protein synthesis and many classic outcome measures in mouse and fly FXS models.
“have demonstrated that dampening mGluR5 signalling rescues protein synthesis and many of the classic outcome measures (TABLE 1) used in the mouse and fly models30–35.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [32]
Core FXS mouse deficits, including protein synthesis, dendritic spine density and morphology, long-term depression, and audiogenic seizures, are consistently rescued by more than ten genetic approaches and multiple drug classes.
“One striking conclusion of the broad array of preclinical studies is that these core deficits can be consistently rescued by more than ten genetic approaches and multiple classes of pharmacological compounds including mGluR antagonists (MPEP, fenobam, mavoglurant and CTEP), GABA agonists, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), mechanistic target of rapamycin (mTOR) inhib”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [32]
No human data are available for spinocerebellar ataxia type 1 because no suitable drug for clinical trials exists.
“No human data are available for SCA1 in the absence of a drug suitable for clinical trials30,32,37.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [32]
Treatment with an mGluR5 antagonist in young adult or fully adult mice produced comprehensive correction of Fmr1-knockout phenotypes.
“Moreover, a comprehensive correction of Fmr1-KO phenotypes was achieved with mGluR5 antagonist treatment of young adult or fully adult mice30,32.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [32]
In Fmr1-knockout mice, mGluR antagonists, GABAB agonists, and gene reinstatement beginning in young adult or adult mice can fully correct most behavioural, physiological, biochemical, and neuroanatomical alterations.
“treatment with mGluR antagonists (mavoglurant) and GABAB agonists (arbaclofen), as well as gene reinstatement in Fmr1-KO mice starting in young adult or adult mice, can fully correct most behavioural, physiological, biochemical and neuroanatomical alterations30,32,37.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [32]
A long-acting mGluR5 antagonist showed efficacy in adult Fmr1-KO mice.
“This study reported efficacy of a long-acting mGluR5 antagonist in adult Fmr1-KO mice.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [32]
Fragile-X pathway-correcting therapies have shown promise in mice and are in Phase II trials.
“the emergence of therapies designed to correct specific pathways disrupted in Fragile-X; these have shown promise in mouse models [89] and are currently undergoing Phase II clinical trials.”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [89]
Long-term use of the mGluR5 antagonist CTEC in adult animals corrected elevated hippocampal long-term depression, protein synthesis, spine dysmorphogenesis, overactive ERK and mTOR signaling, and partially corrected macroorchidism.
“Long term use of a similar mGluR5 antagonist, CTEC, in adult animals corrected elevated hippocampal LTD, protein synthesis, spine dysmorphogenesis, overactive ERK and mTOR signaling, and partially corrected macroorchidism (108).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [108]
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First glimpses of the neurobiology of autism spectrum disorder
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NNZ-2566, a novel analog of (1–3) IGF-1, as a potential therapeutic agent for fragile X syndrome
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Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress
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- Authors
- Michalon, A., Sidorov, M., Ballard, T. M., Ozmen, L., Spooren, W., Wettstein, J. G., Jaeschke, G., Bear, M. F., & Lindemann, L.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Bear, Mark F.
- Lindemann, Lothar
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 74
- Issue
- 1
- Pages
- 49-56
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC8822597
- OpenAlex
- W2045611288
- Cited by
- 489
- References
- 39
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 10 · 2023: 20 · 2022: 19 · 2021: 36 · 2020: 33 · 2019: 31 · 2018: 23 · 2017: 53 · 2016: 52 · 2015: 43 · 2014: 46 · 2013: 58 · 2012: 38
- FWCI
- 35.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Elsevier eBooks
- Funders
- National Institute of Mental Health (R21MH090452)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- fragile X syndrome, mGlu5 receptor, CTEP, Fmr1 knockout mice, pharmacological rescue, intellectual disability, long-term depression, protein synthesis, audiogenic seizures, dendritic spine density, ERK signaling, mTOR signaling, macroorchidism, cognitive impairment, auditory hypersensitivity, long-term treatment
- MeSH terms
- Age Factors, Animals, Disease Models, Animal, Drug Administration Schedule, Fragile X Syndrome, Hippocampus, Imidazoles, Male, Phenotype, Pyridines, Receptors, Metabotropic Glutamate, Mice, Knockout, Excitatory Amino Acid Antagonists, Mice, Fragile X Messenger Ribonucleoprotein 1, Receptor, Metabotropic Glutamate 5
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