new role of atm in controlling gabaergic tone during development

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ATM Protein Kinase: Old and New Implications in Neuronal Pathways and Brain Circuitry

Despite that the human autosomal recessive disease ataxia telangiectasia (A-T) is a rare pathology, interest in the function of ataxia-telangiectasia mutated protein (ATM) is extensive. From a clinical point of view, the role of ATM in the central nervous system (CNS) is the most impacting, as motor disability is the predominant symptom affecting A-T patients. Coherently, spino-cerebellar neurodegeneration is the principal hallmark of A-T and other CNS regions such as dentate and olivary nuclei and brain stem are implicated in A-T pathophysiology. Recently, several preclinical studies also highlighted the involvement of ATM in the cerebral cortex and hippocampus, thus extending A-T symptomatology to new brain areas and pathways. Here, we review old and recent evidence that largely demonstrates not only the historical ATM account in DNA damage response and cell cycle regulation, but the multiple pathways through which ATM controls oxidative stress homeostasis, insulin signalling pathways, epigenetic regulation, synaptic transmission, and excitatory–inhibitory balance. We also summarise recent evidence on ATM implication in neurological and cognitive diseases beyond A-T, bringing out ATM as new pathological substrate and potential therapeutic target

ATM rules neurodevelopment and glutamatergic transmission in the hippocampus but not in the cortex

Abstract Interest in the function of ataxia-telangiectasia-mutated protein (ATM) is extensively growing as evidenced by preclinical studies that continuously link ATM with new intracellular pathways. Here, we exploited Atm +/− and Atm −/− mice and demonstrate that cognitive defects are rescued by the delivery of the antidepressant Fluoxetine (Fluox). Fluox increases levels of the chloride intruder NKCC1 exclusively at hippocampal level suggesting an ATM context-specificity. A deeper investigation of synaptic composition unveils increased Gluk-1 and Gluk-5 subunit-containing kainate receptors (KARs) levels in the hippocampus, but not in the cortex, of Atm +/− and Atm −/− mice. Analysis of postsynaptic fractions and confocal studies indicates that KARs are presynaptic while in vitro and ex vivo electrophysiology that are fully active. These changes are (i) linked to KCC2 activity, as the KCC2 blockade in Atm +/− developing neurons results in reduced KARs levels and (ii) developmental regulated. Indeed, the pharmacological inhibition of ATM kinase in adults produces different changes as identified by RNA-seq investigation. Our data display how ATM affects both inhibitory and excitatory neurotransmission, extending its role to a variety of neurological and psychiatric disorders

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 (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

Maternal Immune Activation Delays Excitatory-to-Inhibitory Gamma-Aminobutyric Acid Switch in Offspring

Background: The association between maternal infection and neurodevelopmental defects in progeny is well established, although the biological mechanisms and the pathogenic trajectories involved have not been defined. Methods: Pregnant dams were injected intraperitoneally at gestational day 9 with polyinosinic:polycytidylic acid. Neuronal development was assessed by means of electrophysiological, optical, and biochemical analyses. Results: Prenatal exposure to polyinosinic:polycytidylic acid causes an imbalanced expression of the Na+-K+-2Cl- cotransporter 1 and the K+-Cl- cotransporter 2 (KCC2). This results in delayed gamma-aminobutyric acid switch and higher susceptibility to seizures, which endures up to adulthood. Chromatin immunoprecipitation experiments reveal increased binding of the repressor factor RE1-silencing transcription (also known as neuron-restrictive silencer factor) to position 509 of the KCC2 promoter that leads to downregulation of KCC2 transcription in prenatally exposed offspring. Interleukin-1 receptor type I knockout mice, which display braked immune response and no brain cytokine elevation upon maternal immune activation, do not display KCC2/Na+-K+-2Cl- cotransporter 1 imbalance when implanted in a wild-type dam and prenatally exposed. Notably, pretreatment of pregnant dams with magnesium sulfate is sufficient to prevent the early inflammatory state and the delay in excitatory-to-inhibitory switch associated to maternal immune activation. Conclusions: We provide evidence that maternal immune activation hits a key neurodevelopmental process, the excitatory-to-inhibitory gamma-aminobutyric acid switch; defects in this switch have been unequivocally linked to diseases such as autism spectrum disorder or epilepsy. These data open the avenue for a safe pharmacological treatment that may prevent the neurodevelopmental defects caused by prenatal immune activation in a specific pregnancy time window