Kv2.1-Kv6.4 subunits deficiency impairs inhibitory signaling and visual circuit dynamics in zebrafish

Abstract

Voltage-gated potassium channels (Kv) play a crucial role in maintaining the cells resting potential. Mutations in the Kv2.1 voltage-gated potassium channel are associated with developmental epileptic encephalopathy. Previous analysis of the loss-of-function zebrafish mutants kcnb1sq301 and kcng4bwaw304, which affect genes that encode Kv2.1 subunits (the subunit Kcnb1 and the modulatory subunit Kcng4b), has shown that they play an antagonistic role in the development of hollow organs, such as the brain and ear. In this study, we investigated the behavioral effects of these mutations. Under normal light conditions, both mutants exhibited reduced activity at 5 days post-fertilization. However, exposure to a low concentration of 5 mM of the chemoconvulsant pentylenetetrazole increased their locomotor activity and induced seizures. Quantitative RT-PCR (qRT-PCR) analysis of the mutants revealed an increase in the transcript levels of c-fos and gad2, and a decrease in a transcript level of gabra1. This suggests that mutations cause a disruption to inhibitory neurotransmission. Local field potential recordings from the optic tectum of the mutants under baseline conditions showed an increase in spontaneous electrical activity. The kcnb1 mutant is photosensitive and experiences freezing episodes under high-intensity light. Together, these findings suggest that defects in Kv2.1 subunits impact both locomotor behavior and light-evoked responses.