Mistrafficking of KCC2 promotes hyperexcitability in hippocampal circuitry in a murine model of Christianson Syndrome

Authors

Mustian, J., Qiu, H., Gao, A. Y., Dang, C. L., Vasegh, S. E., Castagner, B., Orlowski, J., Sharif-Naeini, R., McKinney, R. A.

Abstract

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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 14 Sep 2026.

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