Inhibitory interneurons mediate autism-associated behaviors via 4E-BP2

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-09, Vol.116 (36), p.18060-18067
• Main Authors: Wiebe, Shane, Nagpal, Anmol, Truong, Vinh T., Park, Jeehyun, Skalecka, Agnieszka, He, Alexander J., Gamache, Karine, Khoutorsky, Arkady, Gantois, Ilse, Sonenberg, Nahum
• Format: Article
• Language: English
• Subjects: Abnormalities; Animals; Astrocytes; Astrocytes - metabolism; Astrocytes - pathology; Autism; Autistic Disorder - genetics; Autistic Disorder - metabolism; Autistic Disorder - pathology; Behavior, Animal; Biological Sciences; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Clonal deletion; Eukaryotic Initiation Factors - deficiency; Forebrain; GABAergic Neurons - metabolism; GABAergic Neurons - pathology; Glial Fibrillary Acidic Protein - genetics; Glial Fibrillary Acidic Protein - metabolism; Glutamate Decarboxylase - genetics; Glutamate Decarboxylase - metabolism; Glutamatergic transmission; Grooming; Interneurons; Interneurons - metabolism; Interneurons - pathology; Marble; Mice; Mice, Knockout; Neurons; Protein Biosynthesis; Social factors; Social interaction; Translation; Vocalization behavior; γ-Aminobutyric acid
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1908126116

Translational control plays a key role in regulation of neuronal activity and behavior. Deletion of the translational repressor 4E-BP2 in mice alters excitatory and inhibitory synaptic functions, engendering autistic-like behaviors. The contribution of 4E-BP2-dependent translational control in excitatory and inhibitory neurons and astrocytic cells to these behaviors remains unknown. To investigate this, we generated cell-type-specific conditional 4E-BP2 knockout mice and tested them for the salient features of autism, including repetitive stereotyped behaviors (self-grooming and marble burying), sociability (3-chamber social and direct social interaction tests), and communication (ultrasonic vocalizations in pups). We found that deletion of 4E-BP2 in GABAergic inhibitory neurons, defined by Gad2, resulted in impairments in social interaction and vocal communication. In contrast, deletion of 4E-BP2 in forebrain glutamatergic excitatory neurons, defined by Camk2a, or in astrocytes, defined by Gfap, failed to cause autistic-like behavioral abnormalities. Taken together, we provide evidence for an inhibitory-cell-specific role of 4E-BP2 in engendering autism-related behaviors.