Nieprawidłowe transportowanie KCC2 prowadzi do nadpobudliwości obwodów hipokampa w modelu myśim syndromu Christiansona

How endosomal trafficking shapes inhibitory neurotransmission remains poorly understood, despite both processes being linked independently to epilepsy and neurodevelopmental disease. Christianson syndrome (CS), an X-linked neurodevelopmental disorder, represents a potential tractable condition to investigate such coupled processes. CS is caused by loss-of-function mutations in the SLC9A6 gene which encodes the organellar (Na+, K+)/H+ exchanger NHE6 isoform whose loss overacidifies recycling endosomes and disrupts cargo delivery. Prior work has emphasized NHE6's role in excitatory neurons and glia; whether endosomal dysfunction reshapes inhibitory circuits and thereby drives the early treatment-resistant epilepsy that defines CS has not been addressed. Using Nhe6 -/Y mice, we identify a previously unrecognized endosomal-to-inhibitory axis: NHE6 is required for the surface delivery and stability of the neuron-specific potassium-chloride co-transporter KCC2 (encoded by SLC12A5 ) that sets the driving force for GABAergic inhibition. Loss of NHE6 produces developmental downregulation and mistargeting of KCC2 in hippocampal neurons, impaired chloride homeostasis, and circuit-level hyperexcitability in response to a subthreshold convulsant challenge. These results recast CS epilepsy not as a downstream consequence of excitatory dysfunction but as a primary failure of inhibitory development driven by endosomal mistrafficking. More broadly, they establish endosomal pH regulation as a determinant of KCC2 biology; a node implicated across genetic and acquired epilepsies. Pharmacologically restoring KCC2 function therefore offers a mechanism-based therapeutic strategy for CS, and likely for the broader class of disorders in which endosomal trafficking and inhibitory imbalance converge.