Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism

Jill L Silverman, Daniel G. Smith, Stacey J Sukoff Rizzo, Michael N. Karras, Sarah M. Turner, Seda S. Tolu, Dianne K. Bryce, Deborah L. Smith, Kari Fonseca, Robert H. Ring, Jacqueline Crawley

Research output: Contribution to journalArticle

162 Citations (Scopus)

Abstract

Neurodevelopmental disorders such as autism and fragile X syndrome were long thought to be medically untreatable, on the assumption that brain dysfunctions were immutably hardwired before diagnosis. Recent revelations that many cases of autism are caused by mutations in genes that control the ongoing formation and maturation of synapses have challenged this dogma. Antagonists of metabotropic glutamate receptor subtype 5 (mGluR5), which modulate excitatory neurotransmission, are in clinical trials for fragile X syndrome, a major genetic cause of intellectual disabilities. About 30% of patients with fragile X syndrome meet the diagnostic criteria for autism. Reasoning by analogy, we considered the mGluR5 receptor as a potential target for intervention in autism. We used BTBR T+tf/J (BTBR) mice, an established model with robust behavioral phenotypes relevant to the three diagnostic behavioral symptoms of autism - unusual social interactions, impaired communication, and repetitive behaviors - to probe the efficacy of a selective negative allosteric modulator of the mGluR5 receptor, GRN-529. GRN-529 reduced repetitive behaviors in three cohorts of BTBR mice at doses that did not induce sedation in control assays of open field locomotion. In addition, the same nonsedating doses reduced the spontaneous stereotyped jumping that characterizes a second inbred strain of mice, C58/J. Further, GRN-529 partially reversed the striking lack of sociability in BTBR mice on some parameters of social approach and reciprocal social interactions. These findings raise the possibility that a single targeted pharmacological intervention may alleviate multiple diagnostic behavioral symptoms of autism.

Original languageEnglish (US)
Article number131ra51
JournalScience Translational Medicine
Volume4
Issue number131
DOIs
StatePublished - Apr 25 2012
Externally publishedYes

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Metabotropic Glutamate 5 Receptor
Autistic Disorder
Fragile X Syndrome
Behavioral Symptoms
Interpersonal Relations
Inbred Strains Mice
Locomotion
Synaptic Transmission
Intellectual Disability
Synapses
Communication
Clinical Trials
Pharmacology
Phenotype
Mutation
Brain
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. / Silverman, Jill L; Smith, Daniel G.; Rizzo, Stacey J Sukoff; Karras, Michael N.; Turner, Sarah M.; Tolu, Seda S.; Bryce, Dianne K.; Smith, Deborah L.; Fonseca, Kari; Ring, Robert H.; Crawley, Jacqueline.

In: Science Translational Medicine, Vol. 4, No. 131, 131ra51, 25.04.2012.

Research output: Contribution to journalArticle

Silverman, Jill L ; Smith, Daniel G. ; Rizzo, Stacey J Sukoff ; Karras, Michael N. ; Turner, Sarah M. ; Tolu, Seda S. ; Bryce, Dianne K. ; Smith, Deborah L. ; Fonseca, Kari ; Ring, Robert H. ; Crawley, Jacqueline. / Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. In: Science Translational Medicine. 2012 ; Vol. 4, No. 131.
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