Autism spectrum disorders were once thought to be untreatable. However, in 2012, researchers from F. Hoffmann-La Roche, Switzerland, and the Massachusetts Institute of Technology, Cambridge, MA, reported reversing fragile X symptoms in mice, even after the disease was well established. They did this by administering an antagonist of the metabotropic glutamate receptor 5 (mGluR5) to the mice. In this article, we report that a collaborative research team comprised of scientists from the National Institute of Mental Health (NIMH), Bethesda, Md., and Pfizer Worldwide Research and Development, Groton, Conn., used a different mGluR5 antagonist to mitigate autism-like behaviors in two mouse strains: a well-known model of autism, BTBR T+ tf/J (BTBR, 002282), and C58/J (C58, 000669) (Silverman et al. 2012). The findings by these researchers suggest that neurodevelopmental diseases are indeed treatable pharmacologically.
Autism spectrum disorders
In the United States, ASDs affect about one in every 88 children, and their incidence appears to be rising. ASDs usually refer to autism, Asperger syndrome and pervasive developmental disorders not otherwise specified (PDD-NOS). Other neurodevelopmental disorders with high comorbidity for autism, including Rett syndrome, fragile X syndrome and tuberosis sclerosis complex, are often categorized as ASDs. Diagnostic symptoms include poor social and communication skills, stereotyped or repetitive behaviors, few interests, and, in some cases, cognitive deficits. The term “spectrum” alludes to the range of symptom severity among ASDs and among people with the same ASD. Currently, ASDs cannot be cured, but some of the symptoms can be alleviated by medications, and behavioral therapies can improve life skills dramatically (National Institute of Child Health & Human Development).
GRN-529 ameliorates autistic behaviors in mice
GRN-529 is a specific negative allosteric modulator of mGluR5, suppressing the actions of glutamate, the brain’s major neurotransmitter. The NIMH and Pfizer researchers tested the hypothesis that GRN-529 could reverse social deficits and repetitive grooming in BTBR mice and stereotyped jumping in C58 mice. As in humans, the genetic reasons for the autism-like behaviors in these mice are unknown.
Here’s what the NIMH/Pfizer team found:
The BTBR mouse exhibits several autism-relevant behaviors, including low social approach and reciprocal social interactions, unusual vocalizations, and high levels of repetitive self-grooming. A study by Gould et al. (2011) suggests that its autistic behaviors are due to serotonin defects. Extensive phenotypic and genotypic data are available for this mouse in the Mouse Phenome Database.GRN-529 reduces the amount of repetitive self-grooming and repetitive digging by BTBR mice.
Two other mGluR5 antagonists, 2-methyl- 6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP), also reduce repetitive self-grooming in BTBR mice.
GRN-529 dose-dependently reduces repetitive jumping in C58 mice, almost eliminating it at higher doses.
GRN-529 increases sociability – time spent sniffing a new mouse instead of a new object, nose-to-nose sniffing and overall social contact – in BTBR mice.
None of the mGluR5 antagonists tested adversely affect C57BL/6J (B6, 000664) controls.
GRN-529 does not act as a sedative or stimulant in any of the mice tested.
In summary, the NIMH and Pfizer researchers demonstrated that negatively modulating mGluR5 mitigates poor sociability and repetitive behaviors in two different mouse models. These aberrant behaviors are relevant to the first and third diagnostic symptoms of autism in humans. The findings suggest that mGluR5 antagonists also could mitigate symptoms of neurodevelopmental disorders in humans.
