The downregulation of Kv1 channels in Lgi1-/-mice is accompanied by a profound modification of its interactome and a parallel decrease in Kv2 channels

Abstract

In animal models of LGI1-dependent autosomal dominant lateral temporal lobe epilepsy, Kv₁ channels are downregulated, suggesting their crucial involvement in epileptogenesis. The molecular basis of Kv₁ 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 Kv₁ remains unknown. In this study we analyse by immunofluorescence the modifications in neuronal Kv_1.1 and Kv_1.2 distribution throughout the hippocampal formation of LGI1 knock-out mice. We show that Kv₁ downregulation is not restricted to the axonal compartment, but also takes place in the somatodendritic region and is accompanied by a drastic decrease in Kv₂ expression levels. Moreover, we find that the downregulation of these Kv channels is associated with a marked increase in bursting patterns. Finally, mass spectrometry uncovered key modifications in the Kv₁ interactome that highlight the epileptogenic implication of Kv₁ downregulation in LGI1 knock-out animals.

Keywords: Autosomal-dominant lateral temporal lobe epilepsy; Kv(1) channels; Kv(2) channels; Leucine-rich glioma-inactivated 1 (LGI1); Limbic encephalitis; Proteomic.