Abstract
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.
Highlights
In several developmental diseases such as autism, Down syndrome, Dravet syndrome, Rett syndrome, perinatal neuroinflammation, and epilepsy, an altered GABA-mediated inhibition has been addressed [1,2,3,4,5], as well as an imbalanced excitatory/inhibitory ratio (E/I balance) [6,7,8]
We demonstrate that the higher KCC2 expression achieved by the inhibition of ataxia telangiectasia mutated (ATM) kinase occurs through (a) the promotion of the activity of the early growth response 4 (Egr4) on Kcc2b promoter and (b) the increased expression of the epigenetic regulator Mecp2
In order to unveil the possible involvement of ATM in autism spectrum disorders (ASD), we took advantage of 2 different animal models, Mecp2y/– mice and mice prenatally exposed to valproic acid (VPA), as genetically and pharmacologically linked models of autism
Summary
In several developmental diseases such as autism, Down syndrome, Dravet syndrome, Rett syndrome, perinatal neuroinflammation, and epilepsy, an altered GABA-mediated inhibition has been addressed [1,2,3,4,5], as well as an imbalanced excitatory/inhibitory ratio (E/I balance) [6,7,8]. Whereas glutamate mediates neuronal depolarization along life, at the early stages of neuronal development, GABA acts as an excitatory neurotransmitter rather than inhibitory [9,10,11,12,13], directly evoking action potentials and raising intracellular calcium levels [12, 14, 15]. This excitatory action of GABA depends on the expression of the sodium-potassium-chloride cotransporter NKCC1, which maintains the high intracellular chloride concentration in immature neurons [9]. In line with these pivotal effects, impaired KCC2 expression or function associates to the generation of neurodevelopmental diseases, and KCC2 enhancement is the basis of the new therapeutic strategy for these conditions [16]
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