Erbin Regulates Neuronal Hyperexcitability and Seizure Susceptibility in Temporal Lobe Epilepsy

Temporal lobe epilepsy (TLE) is a common intractable form of epilepsy, but the underlying mechanisms remain elusive. Here, we report the upregulation of the postsynaptic scaffolding protein Erbin in epileptic foci from human patients with TLE and in a pilocarpine-induced mouse model. We subsequently modulated Erbin levels in vivo after status epilepticus. Erbin knockdown resulted in less frequent and shorter spontaneous recurrent seizures, whereas Erbin overexpression exacerbated them. Erbin modulation also produced significant changes in neuronal excitability, including action potentials, miniature excitatory postsynaptic currents, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-mediated currents. Furthermore, Erbin knockdown decreased dendritic spine density and the density of excitatory synapses in the dentate gyrus inner molecular layer, whereas Erbin overexpression increased the density of excitatory synapses. Overall, we provide the first evidence that Erbin is upregulated in TLE and exerts a proepileptic effect by controlling synaptic function and structure, identifying it as a promising therapeutic target.