Stoppel LJ, Kazdoba TM, Schaffler MD, Preza AR, Heynen A, Crawley JN, Bear MF. R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice. Neuropsychopharmacology. 2017 Oct 6. Epublished.
Human chromosome 16p11.2 microdeletion is among the most common gene copy number variations (CNVs) known to confer risk for intellectual disability (ID) and autism spectrum disorder (ASD), and affects an estimated 3 in 10 000 people. Caused by a single copy deletion of ~27 genes, 16p11.2 microdeletion syndrome is characterized by ID, impaired language, communication and socialization skills, and ASD. Studies in animal models where a single copy of the syntenic 16p11.2 region has been deleted have revealed morphological, behavioral, and electrophysiological abnormalities. Previous studies suggested the possibility of some overlap in the mechanisms of pathophysiology in 16p11.2 microdeletion syndrome and fragile X syndrome. Improvements in fragile X phenotypes have been observed following chronic treatment with R-baclofen, a selective agonist of GABAB receptors. We were therefore motivated to investigate the effects of chronic oral R-baclofen administration in two independently generated mouse models of 16p11.2 microdeletion syndrome. In studies performed across two independent laboratories we found that chronic activation of GABAB receptors improved performance on a series of cognitive and social tasks known to be impaired in two different 16p11.2 deletion mouse models. Our findings suggest that R-baclofen may have clinical utility for some of the core symptoms of human 16p11.2 microdeletion syndrome.
Human chromosome 16p11.2 deletion syndrome is caused by the absence of about 27 genes on chromosome 16. This deletion is characterized by intellectual disability; impaired language, communication, and socialization skills; and autism spectrum disorder or ASD.
Research from the laboratories of Mark Bear at MIT and Jacqueline Crawley at the University of California at Davis, has identified a potential therapeutic for ASD. Researchers found that R-Baclofen reverses cognitive deficits and improves social interactions in two lines of 16p11.2 deletion mice…
“Our collaborative teams found that treatment with the drug R-baclofen improved scores on several learning and memory tasks, and on a standard assay of social behavior, in 16p11.2 mutant mice,” says Crawley, co-senior author of the paper along with Bear.
“This unique corroboration of findings by two independent labs, using two distinct lines of mice with the same mutation, increases confidence that R-baclofen may be an effective pharmacological treatment for some of the symptoms of human 16p11.2 deletion syndrome, including intellectual impairment and autism,” she says.
“These findings are particularly exciting on two fronts,” says Bear, who is the Picower Professor of Neuroscience at MIT. “First, the results show that diverse genetic causes of intellectual disability and autism may converge on a limited number of pathophysiological processes that can be ameliorated pharmacologically. Thus, a treatment for one genetically defined disorder may be beneficial for another with phenotypic overlap. Second, R-Baclofen has a well-understood safety profile and is well-tolerated in children and adults, making clinical studies feasible in the near future.”
One of the genes in the 16p11.2 deletion region regulates the inhibitory neurotransmitter GABA. Researchers tested the hypothesis that increasing GABA neurotransmission using R-baclofen, which binds to GABA-B receptors, could reverse analogous behavioral symptoms in a mouse model of 16p11.2 deletion syndrome.
In the current paper, researchers report the results of animal model studies using two independently derived lines of mutant mice, each missing a chromosomal region analogous to human 16p11.2. Normal and mutant mice at both labs were tested after receiving R-baclofen in their drinking water on three tasks: novel object recognition, object location memory, and contextual recognition learning and memory. In addition, R-baclofen treated mutant mice scored better after treatment on each cognitive task than the untreated mutant mice. R-baclofen also increased scores on a standard assay of mouse social behaviors — male-female reciprocal social interactions — in the 16p11.2 mutant mice.