MGluR5 Modulation of Behavioral and Epileptic Phenotypes in a Mouse Model of Tuberous Sclerosis Complex

Elyza Kelly, Samantha M. Schaeffer, Sameer C. Dhamne, Jonathan O. Lipton, Lothar Lindemann, Michael Honer, Georg Jaeschke, Chloe E. Super, Stephen Ht Lammers, Meera E. Modi, Jill L Silverman, John R. Dreier, David J. Kwiatkowski, Alexander Rotenberg, Mustafa Sahin

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1457-1465
Number of pages9
JournalNeuropsychopharmacology
Volume43
Issue number6
DOIs
StatePublished - May 1 2018

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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    Kelly, E., Schaeffer, S. M., Dhamne, S. C., Lipton, J. O., Lindemann, L., Honer, M., Jaeschke, G., Super, C. E., Lammers, S. H., Modi, M. E., Silverman, J. L., Dreier, J. R., Kwiatkowski, D. J., Rotenberg, A., & Sahin, M. (2018). MGluR5 Modulation of Behavioral and Epileptic Phenotypes in a Mouse Model of Tuberous Sclerosis Complex. Neuropsychopharmacology, 43(6), 1457-1465. https://doi.org/10.1038/npp.2017.295