Impairment of GABAergic system has been reported in epilepsy, autism, ADHD and schizophrenia. We recently demonstrated that Ataxia Telangiectasia Mutated (ATM) shapes directly the development of GABAergic system. Here, we show for the first time how the abnormal expression of ATM impacts the pathological condition of autism. We exploit two different animal models of autism, the Mecp2y/- mouse model of Rett syndrome, and mice prenatally exposed to valproic acid, and found increased ATM levels. Accordingly, the treatment with the specific ATM kinase inhibitor KU55933 (KU) normalises molecular, functional and behavioural defects in these mouse models such as the i) delayed GABAergic development, ii) hippocampal hyper-excitability, iii) low cognitive performances, iv) social impairments. Mechanistically, we demonstrate that KU administration to wild type hippocampal neurons leads to i) higher Egr4 activity on Kcc2b promoter, ii) increased expression of Mecp2, iii) potentiated GABA-transmission. These results provide evidences and molecular substrates for the pharmacological development of ATM inhibition in autism spectrum disorders.

The DNA repair protein ATM as target in autism spectrum disorder / L. Pizzamiglio, E. Focchi, C. Cambria, L. Ponzoni, S. Ferrara, F. Bifari, G. Desiato, N. Landsberger, L. Murru, M. Passafaro, M. Sala, M. Matteoli, E. Menna, F. Antonucci. - In: JCI INSIGHT. - ISSN 2379-3708. - (2020 Dec 29). [Epub ahead of print]

The DNA repair protein ATM as target in autism spectrum disorder

L. Pizzamiglio
Primo
;
E. Focchi
Secondo
;
C. Cambria;F. Bifari;N. Landsberger;M. Sala;M. Matteoli;E. Menna
Penultimo
;
F. Antonucci
Ultimo
2020-12-29

Abstract

Impairment of GABAergic system has been reported in epilepsy, autism, ADHD and schizophrenia. We recently demonstrated that Ataxia Telangiectasia Mutated (ATM) shapes directly the development of GABAergic system. Here, we show for the first time how the abnormal expression of ATM impacts the pathological condition of autism. We exploit two different animal models of autism, the Mecp2y/- mouse model of Rett syndrome, and mice prenatally exposed to valproic acid, and found increased ATM levels. Accordingly, the treatment with the specific ATM kinase inhibitor KU55933 (KU) normalises molecular, functional and behavioural defects in these mouse models such as the i) delayed GABAergic development, ii) hippocampal hyper-excitability, iii) low cognitive performances, iv) social impairments. Mechanistically, we demonstrate that KU administration to wild type hippocampal neurons leads to i) higher Egr4 activity on Kcc2b promoter, ii) increased expression of Mecp2, iii) potentiated GABA-transmission. These results provide evidences and molecular substrates for the pharmacological development of ATM inhibition in autism spectrum disorders.
Development; Molecular pathology; Mouse models; Neurological disorders; Neuroscience
Settore BIO/14 - Farmacologia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/803621
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