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

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 (Mecp2(v)(/-)) 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 KU5S933 (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.

Automated summary

This study demonstrates the role of ATM in the pathogenesis of autism, showing how abnormal expression of ATM affects the development of the GABAergic system and leads to behavioral impairments. Treatment with the specific ATM kinase inhibitor KU can normalize molecular, functional, and behavioral defects in mouse models of autism, supporting the potential of ATM inhibition in the pharmacological development for autism spectrum disorders.