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Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice
Aubin Michalon1, Michael Sidorov, Theresa M Ballard
1Discovery Neuroscience, Pharmaceuticals Division, F. Hoffmann-La Roche, CH-4070 Basel, Switzerland.
Abstract:
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.
Insights
Fragile X syndrome (FXS) treatment with an mGlu5 inhibitor reversed established disease phenotypes in mice. This suggests potential for pharmacological intervention in FXS patients, even after symptom onset.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Fragile X syndrome (FXS) is a leading inherited cause of intellectual disability.
- The role of metabotropic glutamate receptor 5 (mGluR5) in FXS pathogenesis is implicated.
- Reversing established FXS phenotypes pharmacologically remains an open question.
Purpose of the Study:
- To investigate if mGluR5 inhibition can reverse established FXS phenotypes in a mouse model.
- To evaluate the efficacy of the selective mGluR5 inhibitor CTEP.
Main Methods:
- Utilized the Fmr1 knockout mouse model for FXS.
- Administered acute and chronic treatment with the mGluR5 inhibitor CTEP.
- Assessed various physiological and behavioral outcomes, including synaptic function, seizures, cognition, and molecular signaling.
Main Results:
- Acute CTEP treatment normalized hippocampal long-term depression, protein synthesis, and audiogenic seizures.
- Chronic CTEP treatment rescued cognitive deficits, auditory hypersensitivity, and aberrant dendritic spine density.
- Signaling pathways (ERK, mTOR) and macroorchidism were also positively impacted by chronic treatment.
Conclusions:
- Pharmacological mGluR5 inhibition can comprehensively reverse established FXS phenotypes in adult mice.
- Intervention is effective even after the phenotype has developed, offering hope for clinical translation.
- Findings support ongoing clinical trials investigating mGluR5 inhibitors for FXS treatment.
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