Molecular Basis of Kv1 Channel Downregulation and Its Epileptogenic Implications in Lgi1 Knock-out Mice

The Kv 1 members (KCNA, Shaker) of the voltage-gated potassium channels are implicated in determining key functional neuronal properties from spike generation at axonal initial segments to the control of synaptic strength at nerve terminals. In animal models of LGI1-dependent autosomal dominant lateral temporal lobe epilepsy (ADTLE), Kv 1 channels are downregulated, suggesting their crucial involvement in epileptogenesis. The molecular basis of Kv 1 channel-downregulation in LGI1 knock-out mice has not been elucidated and how the absence of this extracellular protein induces an important modification in the expression of Kv 1 remains unknown. In this study we analyse by immunofluorescence the detailed modifications in neuronal Kv 1.1 and Kv 1.2 distribution throughout the hippocampal formation of LGI1 knock-out mice. We show that Kv 1 downregulation is not restricted to the axonal compartment, but also takes place in the somatodendritic region and is accompanied by a drastic decrease in Kv 2 expression levels. Moreover, we find that the downregulation of these Kv channels is associated with an important increase in bursting patterns. Finally, mass spectrometry uncovered key important modifications in the Kv 1 interactome that highlight the epileptogenic implication of Kv 1 downregulation in LGI1 knock-out animals.