The Therapeutic Potential of ATM Inhibition in Rett Syndrome: Insights from Behavioral and Molecular Studies

Ataxia Telangiectasia Mutated (ATM) is a protein known for its role in DNA double-strand break repair. Recent studies have discovered ATM’s new role in regulating KCC2, a crucial potassium chloride co-transporter, which induces the “excitatory-to-inhibitory GABA switch", a fundamental step in the maturation of the GABAergic system. In Rett Syndrome (RTT), a sever neurodevelopmental disorder caused by mutations in the MeCP2 gene, elevated ATM levels in the hippocampus are linked to decreased KCC2 expression, delaying the “GABA switch”, and disrupting excitatory/inhibitory (E/I) balance. This dysfunction contributes to the RTT’s socio-cognitive, motor, and respiratory impairments. Our laboratory investigated the therapeutic potential of ATM inhibition through KU-55933 (KU), an ATM kinase inhibitor, in the Mecp2y/- (KO) mouse model of RTT, with the aim to restore KCC2 levels and correct the GABAergic dysfunction underlying the pathology. Two objectives were addressed: the evaluation of intranasal KU’s effects on socio-cognitive, motor, and respiratory functions, and the examination of the molecular changes associated with RTT and KU treatment. Behavioral assessments, including Y-maze, Novel Object Recognition (NOR), Three-chamber test, Rotarod, and Plethysmograph, revealed that the intranasal KU administration significantly improved hippocampal cognitive functions and ameliorated respiratory abnormalities, such as the number of apneas, which are critical in RTT progression. Furthermore, KU treatment enhanced overall health and survival in RTT mice but had no effects on motor deficits. Biochemical analysis of hippocampal tissues supported the cognitive improvements, showing that KU prevented the decline in KCC2 expression and normalized pathological increases in vGAT levels, a marker for inhibitory synapses, suggesting a correction of the delayed “GABA switch” and of the E/I balance. However, the therapeutic effects of KU were transient, as demonstrated by behavioral data after the washout period, highlighting the need for continuous treatment to maintain these benefits and ensure long-term efficacy. In conclusion, ATM inhibition via KU may represent a novel therapeutic approach for RTT, aimed at mitigating the pathological symptoms by addressing underlying molecular dysfunctions. However, further research is needed to deepen our understanding of the mechanism involved.