Abstract
Drugs targeting metabotropic glutamate receptor 5 (mGluR5) have therapeutic potential in autism spectrum disorders (ASD), including tuberous sclerosis complex (TSC). The question whether inhibition or potentiation of mGluR5 could be beneficial depends, among other factors, on the specific indication. To facilitate the development of mGluR5 treatment strategies, we tested the therapeutic utility of mGluR5 negative and positive allosteric modulators (an mGluR5 NAM and PAM) for TSC, using a mutant mouse model with neuronal loss of Tsc2 that demonstrates disease-related phenotypes, including behavioral symptoms of ASD and epilepsy. This model uniquely enables the in vivo characterization and rescue of the electrographic seizures associated with TSC. We demonstrate that inhibition of mGluR5 corrects hyperactivity, seizures, and elevated de novo synaptic protein synthesis. Conversely, positive allosteric modulation of mGluR5 results in the exacerbation of hyperactivity and epileptic phenotypes. The data suggest a meaningful therapeutic potential for mGluR5 NAMs in TSC, which warrants clinical exploration and the continued development of mGluR5 therapies.
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Acknowledgements
We are indebted to members of the Sahin lab for critical reading of the manuscript.
This study was supported by the BCH Neurodevelopmental Behavioral Core of the Intellectual and Developmental Disabilities Research Center (NIH U54 HD090255), the BCH Translational Neuroscience Center, and the Experimental Neurophysiology Core, Nancy Lurie Marks Family Foundation, and the Boston Children’s Hospital Translational Research Program (to M.S. and A.R.).
Author contributions
Conceived and designed the experiments: A.R., L.L., and M.S.; performed the experiments: E.K., S.M.S., S.C.D., J.O.L., C.E.S., S.H.T.L., and M.H.; analyzed the data: S.C.D., J.O.L., M.E.M., A.R., M.H., and M.S.; contributed reagents/materials/analysis tools: D.J.K., L.L., G.J., J.L.S., and J.R.D.; drafted the article: E.K., S.M.S., S.C.D., L.L., M.E.M., and M.S.; revised the article: E.K., S.M.S., S.C.D., J.O.L., L.L., C.E.S., S.H.T., M.E.M., J.L.S., J.R.D, D.J.K., A.R., and M.S.
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Kelly, E., Schaeffer, S., Dhamne, S. et al. mGluR5 Modulation of Behavioral and Epileptic Phenotypes in a Mouse Model of Tuberous Sclerosis Complex. Neuropsychopharmacol. 43, 1457–1465 (2018). https://doi.org/10.1038/npp.2017.295
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DOI: https://doi.org/10.1038/npp.2017.295
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