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

Abstract

AbstractThe Kv1members (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), Kv1channels are downregulated, suggesting their crucial involvement in epileptogenesis. The molecular basis of Kv1channel-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 Kv1remains unknown. In this study we analyse by immunofluorescence the detailed modifications in neuronal Kv1.1and Kv1.2distribution throughout the hippocampal formation of LGI1 knock-out mice. We show that Kv1downregulation is not restricted to the axonal compartment, but also takes place in the somatodendritic region and is accompanied by a drastic decrease in Kv2expression 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 Kv1interactome that highlight the epileptogenic implication of Kv1downregulation in LGI1 knock-out animals.