ZNRF1-dependent regulation of AKT activity modulates Nav subcellular localization and AIS position in neurons to regulate fear-related behavior.

The axon initial segment (AIS) is a specialized compartment at the proximal axon, characterized by condensed localization of specific cytoskeletal proteins, including Ankyrin G (AnkG) and βIV-spectrin which organize voltage-gated ion channels (VGICs). The location and morphology of the AIS can change in response to neuronal activity; however, the precise mechanisms for the AIS plasticity remain unclear. Previously, we demonstrated that ubiquitin E3 ligase ZNRF1 is localized to presynaptic terminals in cultured hippocampal neurons and may play a role in Ca2+-dependent exocytosis. Here, we show that using ZNRF1 knockout (ZNRF1 KO) mice, ZNRF1-dependent AKT degradation induces AIS shift and increased cell surface localization of voltage-gated sodium channel Nav1.2. We also found that ZNRF1 KO mice exhibit enhanced short-term fear memory and increased contextual fear memory. These findings suggest that ZNRF1 may serve as a novel regulator of AIS localization.