ABSTRACT
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.
Subject(s)
Autistic Disorder/drug therapy , Autistic Disorder/psychology , Baclofen/pharmacology , Chromosome Disorders/drug therapy , Chromosome Disorders/psychology , Cognition Disorders/drug therapy , Intellectual Disability/drug therapy , Intellectual Disability/psychology , Psychotropic Drugs/pharmacology , Social Behavior , Animals , Chromosome Deletion , Chromosomes, Human, Pair 16 , Disease Models, Animal , Female , GABA-B Receptor Agonists/pharmacology , Learning Disabilities/drug therapy , Male , Memory Disorders/drug therapy , Mice, 129 Strain , Mice, Inbred C57BL , Species SpecificityABSTRACT
Synaptic protein synthesis is essential for modification of the brain by experience and is aberrant in several genetically defined disorders, notably fragile X (FX), a heritable cause of autism and intellectual disability. Neural activity directs local protein synthesis via activation of metabotropic glutamate receptor 5 (mGlu5), yet how mGlu5 couples to the intracellular signaling pathways that regulate mRNA translation is poorly understood. Here, we provide evidence that ß-arrestin2 mediates mGlu5-stimulated protein synthesis in the hippocampus and show that genetic reduction of ß-arrestin2 corrects aberrant synaptic plasticity and cognition in the Fmr1-/y mouse model of FX. Importantly, reducing ß-arrestin2 does not induce psychotomimetic activity associated with full mGlu5 inhibitors and does not affect Gq signaling. Thus, in addition to identifying a key requirement for mGlu5-stimulated protein synthesis, these data suggest that ß-arrestin2-biased negative modulators of mGlu5 offer significant advantages over first-generation inhibitors for the treatment of FX and related disorders.
