Activity-dependent degradation of Kv4.2 contributes to synaptic plasticity and behavior in Angelman syndrome model mice.

Abstract

Angelman syndrome (AS) is a severe neurological disorder characterized by intellectual disability, absence of speech, spontaneous seizure, and motor dysfunction. The absence of functional maternally derived UBE3A protein is considered the primary cause of AS, yet the downstream signaling pathways remain elusive. Here, we show the voltage-gated K⁺ channel Kv4.2 as an activity-dependent substrate for UBE3A. We show that UBE3A binding of Kv4.2 at its N terminus, ubiquitinating residue K103, induces activity-induced Kv4.2 protein loss. In a mouse model of AS, we observe elevated Kv4.2 protein level and abolished kainic acid-induced Kv4.2 protein loss. Moreover, deficits in mEPSC frequency and spike-timing-dependent long-term potentiation, as well as certain behaviors including cognitive inflexibility found in AS mice, are rescued when bred with Kv4.2 conditional knockout mice. These findings indicate a UBE3A downstream pathway regulating plasticity and cognitive behaviors and provide potential targets for the treatment of AS.