Loss of functional System x-c uncouples aberrant postnatal neurogenesis from epileptogenesis in the hippocampus of Kcna1-KO mice

Mutations in Kv1.1 (Kcna1) voltage-gated potassium channels in humans and mice generate network hyper -excitability, enhancing aberrant postnatal neurogenesis in the dentate subgranular zone, resulting in epilepsy and hippocampal hypertrophy. While Kcna1 loss stimulates proliferation of progenitor cell subpopulations, the identity of extrinsic molecular triggers linking network hyperexcitability to aberrant postnatal neurogenesis remains incomplete. System x-c (Sxc) is an inducible glutamate/cysteine antiporter that regulates extra -cellular glutamate. Here, we find that the functional unit of Sxc, xCT (Slc7a11), is upregulated in regions of Kcna1 knockout (KO) hippocampus, suggesting a contribution to both hyperplasia and epilepsy. However, Slc7a11 KO suppressed and rescued hippocampal enlargement without altering seizure severity in Kcna1-Slc7a11-KO mice. Microglial activation, but not astrocytosis, was also reduced. Our study identifies Sxc-mediated glutamate homeostasis as an essential non-synaptic trigger coupling aberrant postnatal neurogen-esis and neuroimmune crosstalk, revealing that neurogenesis and epileptogenesis in the dentate gyrus are not mutually contingent events.

Automated summary

Mutations in Kv1.1 voltage-gated potassium channels lead to network hyperexcitability, aberrant postnatal neurogenesis, and hippocampal hypertrophy. This study suggests that Sxc-mediated glutamate homeostasis plays a crucial role in connecting aberrant postnatal neurogenesis and neuroimmune crosstalk, and that neurogenesis and epileptogenesis in the dentate gyrus are not mutually contingent events.