ATM Inhibition in Rett Syndrome: Investigating Hippocampal and Brainstem Circuits

Rett Syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females, caused by mutations in the MECP2 gene. Its hallmark features are cognitive, motor, and respiratory impairments. Recent studies revealed that Ataxia Telangiectasia Mutated (ATM), beyond its role in DNA repair, regulates KCC2, a chloride exporter essential for the developmental GABAergic switch. In RTT models, ATM is abnormally upregulated in the hippocampus, contributing to reduced KCC2 expression and delayed maturation of inhibitory signaling. We previously showed that intranasal administration of the selective ATM inhibitor KU-55933 (KU) in Mecp2y/- (KO) mice improved hippocampal-dependent cognition. Biochemical analyses confirmed that KU preserved KCC2 levels and normalized the expression of vGAT, a marker of inhibitory synapses, suggesting a partial restoration of inhibitory tone. Respiratory abnormalities represent a major clinical burden in RTT and are thought to be related to excessive excitatory tone in brainstem circuits. In our study, we observed a partial restoration of apnea frequency following KU treatment, particularly after treatment cessation. To investigate the neural mechanisms underlying this, we are now focusing on the Kolliker-Fuse (KF) nucleus, a key brainstem center implicated in respiratory rhythm modulation and phase switching. Although its dysfunction has been demonstrated in RTT, the maturation of inhibitory signaling within this nucleus remains unexplored. Given the link between delayed GABA switch and altered excitability in RTT, we hypothesize that similar mechanisms may occur in the KF. Ongoing analyses aim to evaluate KCC2 expression in this area, identified by FOXP2 and NeuN immunolabeling, to provide preliminary insight into inhibitory maturation. In conclusion, our findings support the therapeutic potential of ATM inhibition in RTT, through hippocampal circuit modulation but also by targeting brainstem nuclei involved in autonomic control. Further studies are needed to understand the plasticity induced in the KF and to explore effects in female models, with broader translational relevance.