Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism

Autism-like behaviors in mice were reversed by a negative modulator of a metabotropic glutamate receptor, suggesting a treatment for symptoms of autism spectrum disorders. Treatment of Autism Symptoms in Mice When they are 2 to 5 years old, children with autism start to show unusual social interactions and impaired communication. They may fail to develop relationships with their peers and be unable to interpret nuances of speech and body language. Most show repetitive motor behaviors and restricted interests and can have associated seizures, anxiety, or intellectual impairment. A large number of genes can put people at risk for this disorder, each in a small number of cases, and these genes point to connections between neurons as a vulnerable point in autism. Now, Silverman and colleagues have used two inbred strains of mice that display well-replicated behavioral abnormalities relevant to the diagnostic symptoms of autism and shown that some of these symptoms can be improved with a drug directed at a central glutamate receptor of the brain, mGluR5. The authors used two inbred strains of mice that display robust behaviors relevant to the diagnostic symptoms of autism. BTBR mice show deficits in many types of social interactions and high levels of repetitive self-grooming. C58 repetitively jumps. They used GRN-529, a compound developed by Pfizer that reduces the actions of glutamate, the main excitatory neurotransmitter in the brain. Other mGluR antagonists are showing promise in clinical trials for people with the fragile X mutation, who have both intellectual impairments and autism, so the authors reasoned that an mGluR5 compound might help autistic symptoms. GRN-529 reduced both the repetitive self-grooming in BTBR and the repetitive jumping in C58. Most intriguingly, GRN-529 also improved social behaviors in BTBR in two assays, one for social approach to an unfamiliar mouse and one for social interactions between freely moving pairs of mice. A particular strength of this study is that the authors replicated these beneficial actions of the mGluR5 compound in several separate groups of mice, in two laboratories. Although the path from target identification to effective human treatment is a long and winding road, the discovery of therapeutic efficacy for an mGluR5 negative allosteric modulator in both the repetitive and the social domains in two distinct mouse models is a promising beginning. This single biological target may offer a useful entry point to develop a pharmacological therapy that alleviates many symptoms of autism spectrum disorders. 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.