The DNA repair protein ATM as a target in autism spectrum disorder

• Published in: JCI insight Vol. 6; no. 3
• Main Authors: Pizzamiglio, Lara, Focchi, Elisa, Cambria, Clara, Ponzoni, Luisa, Ferrara, Silvia, Bifari, Francesco, Desiato, Genni, Landsberger, Nicoletta, Murru, Luca, Passafaro, Maria, Sala, Mariaelvina, Matteoli, Michela, Menna, Elisabetta, Antonucci, Flavia
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 08-02-2021; American Society for Clinical investigation
• Subjects: Animals; Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors; Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; Autism Spectrum Disorder - drug therapy; Autism Spectrum Disorder - physiopathology; Autism Spectrum Disorder - psychology; Behavior, Animal - drug effects; Behavior, Animal - physiology; Development; Disease Models, Animal; DNA Repair; Female; GABAergic Neurons - drug effects; GABAergic Neurons - physiology; Hippocampus - drug effects; Hippocampus - metabolism; Humans; K Cl- Cotransporters; Male; Methyl-CpG-Binding Protein 2 - deficiency; Methyl-CpG-Binding Protein 2 - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Morpholines - pharmacology; Neuroscience; Pregnancy; Prenatal Exposure Delayed Effects; Protein Kinase Inhibitors - pharmacology; Pyrones - pharmacology; Rett Syndrome - drug therapy; Rett Syndrome - physiopathology; Rett Syndrome - psychology; Symporters - genetics; Symporters - metabolism; Valproic Acid - toxicity; Development; Molecular pathology; Neuroscience; Mouse models; Neurological disorders
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.133654

Impairment of the GABAergic system has been reported in epilepsy, autism, attention deficit hyperactivity disorder, and schizophrenia. We recently demonstrated that ataxia telangiectasia mutated (ATM) directly shapes the development of the GABAergic system. Here, we show for the first time to our knowledge how the abnormal expression of ATM affects the pathological condition of autism. We exploited 2 different animal models of autism, the methyl CpG binding protein 2-null (Mecp2y/-) mouse model of Rett syndrome and mice prenatally exposed to valproic acid, and found increased ATM levels. Accordingly, treatment with the specific ATM kinase inhibitor KU55933 (KU) normalized molecular, functional, and behavioral defects in these mouse models, such as (a) delayed GABAergic development, (b) hippocampal hyperexcitability, (c) low cognitive performances, and (d) social impairments. Mechanistically, we demonstrate that KU administration to WT hippocampal neurons leads to (a) higher early growth response 4 activity on Kcc2b promoter, (b) increased expression of Mecp2, and (c) potentiated GABA transmission. These results provide evidence and molecular substrates for the pharmacological development of ATM inhibition in autism spectrum disorders.