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

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.

• Authors: 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 N Crawley
• Journal: Science translational medicine (Sci Transl Med) Vol. 4 Issue 131 Pg. 131ra51 (Apr 25 2012) ISSN: 1946-6242 [Electronic] United States
• PMID: 22539775 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Excitatory Amino Acid Antagonists
• GRM5 protein, human
• Grm5 protein, mouse
• Receptor, Metabotropic Glutamate 5
• Receptors, Metabotropic Glutamate

Topics

• Animals
• Behavior, Animal (drug effects)
• Blood-Brain Barrier (metabolism)
• Brain (drug effects, metabolism, physiopathology)
• Capillary Permeability
• Child Development Disorders, Pervasive (drug therapy, metabolism, physiopathology, psychology)
• Child, Preschool
• Disease Models, Animal
• Excitatory Amino Acid Antagonists (blood, pharmacology)
• Female
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Motor Activity (drug effects)
• Receptor, Metabotropic Glutamate 5
• Receptors, Metabotropic Glutamate (antagonists & inhibitors, metabolism)
• Sleep (drug effects)
• Social Behavior
• Stereotyped Behavior
• Time Factors
• Video Recording