The Potentiation of Cortical Pyramidal Neurons Due to the Gain of Function Mutation of Kv.4.2 Channels

Abstract

Kv4.2 channels are a type of K⁺ channel responsible for the early phase of repolarization in an action potential. In 2014, a gain of function (GOF) mutation in these channels was shown to lead to seizures. Since this mutation led to a more sustained K⁺ current in the mutant neurons' repolarizing phase, it is not clear why it would lead to hyperexcitability and not hypoexcitability. It has been shown that the transient silencing of glutamatergic neurons can lead to their potentiation, which is called homeostatic potentiation. This proposal aims to test whether homeostatic potentiation of cortical pyramidal neurons of layer2/3 is the underlying mechanism behind the seizures induced by this mutation. To examine this, three markers of potentiation will be investigated in pyramidal neurons of layer 2/3 in mice that are either wildtype (WT) or mutant for the Kv4.2 GOF mutation. These markers include the excitatory post synaptic current (EPSC), spine density and the AMPA receptor density on the post synaptic density (PSD), which should all increase after potentiation. The results of this research will reveal the mechanism behind this mutation’s effects, potentially leading to the development of targeted pharmacological interventions for the form epilepsy induced by this mutation.