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bioRxiv · 10.64898/2026.01.13.699303

KCC2 Activation Reverses Neurophysiological and Behavioral Deficits in Female Rett Mice

Arshad, M. N.·Ng, S. F. J.·Salar, S.·Abiraman, K.·Nishi, T.·Zhong, Z.·Smalley, J. L.·Davies, P. A.·Moss, S. J.
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Abstract

Rett syndrome is an X-linked neurodevelopmental disorder resulting from mutations in the MeCP2 gene, leading to intellectual disability, impaired motor coordination, decreased sociability, and seizures. Central to the underlying pathophysiology are deficits in synaptic inhibition, which are mediated by hyperpolarizing GABAAR currents. These events develop postnatally and are dependent upon increased neuronal Cl- extrusion mediated by SLC12A5 (KCC2). Therefore, we tested whether its activation modifies the disease phenotypes evident in female MeCP2+/- mice, using OV350, a direct activator of KCC2. OV350 rapidly induced a sustained reduction in EEG power, accompanied by a decrease in the severity of epileptic discharges. Increased motor coordination, sociability, and spatial memory were also observed. Deficits in KCC2 phosphorylation were also seen in MeCP2+/- mice, consistent with reductions in its activity that were also ameliorated by OV350. Thus, KCC2 activation may be efficacious in limiting the impact of Rett syndrome and other neurodevelopmental disorders.

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Arshad, M. N., Ng, S. F. J., Salar, S., Abiraman, K., Nishi, T., Zhong, Z., Smalley, J. L., Davies, P. A., Moss, S. J.. 2026-01-14. KCC2 Activation Reverses Neurophysiological and Behavioral Deficits in Female Rett Mice. https://doi.org/10.64898/2026.01.13.699303

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