Epilepsy-associated gene Nedd4-2 mediates neuronal activity and seizure susceptibility through AMPA receptors

The neural precursor cell expressed developmentally down-regulated gene 4–2,nedd4-2,is an epilepsy-associated gene with at least three missense mutations identified in epileptic patients. nedd4-2 encodes a ubiquitin e3 ligase that has high affinity toward binding and ubiquitinating membrane proteins. it is currently unknown how nedd4-2 mediates neuronal circuit activity and how its dysfunction leads to seizures or epilepsies. in this study,we provide evidence to show that nedd4-2 mediates neuronal activity and seizure susceptibility through ubiquitination of glua1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor,(ampar). using a mouse model,termed nedd4-2andi,in which one of the major forms of nedd4-2 in the brain is selectively deficient,we found that the spontaneous neuronal activity in nedd4-2andicortical neuron cultures,measured by a multiunit extracellular electrophysiology system,was basally elevated,less responsive to ampar activation,and much more sensitive to ampar blockade when compared with wild-type cultures. when performing kainic acid-induced seizures in vivo,we showed that elevated seizure susceptibility in nedd4-2andimice was normalized when glua1 is genetically reduced. furthermore,when studying epilepsy-associated missense mutations of nedd4-2,we found that all three mutations disrupt the ubiquitination of glua1 and fail to reduce surface glua1 and spontaneous neuronal activity when compared with wild-type nedd4-2. collectively,our data suggest that impaired glua1 ubiquitination contributes to nedd4-2-dependent neuronal hyperactivity and seizures. our findings provide critical information to the future development of therapeutic strategies for patients who carry mutations of nedd4-2. © 2017 zhu et al.