HAP1 Modulates Epileptic Seizures by Regulating GABA_AR Function in Patients with Temporal Lobe Epilepsy and in the PTZ-Induced Epileptic Model

The number of gamma-aminobutyric acid type A receptors (GABA(A)Rs) expressed on the surface membrane and at synaptic sites is implicated in the enhanced excitation of neuronal circuits and abnormal network oscillations in epilepsy. Huntingtin-associated protein 1 (HAP1), a key mediator of pathological alterations in protein trafficking, directly interacts with GABA(A)Rs and facilitates their recycling back to synapses after internalization from the surface; thus, HAP1 regulates the strength of inhibitory synaptic transmission. Here, we show that HAP1 modulates epileptic seizures by regulating GABA(A)R function in patients with temporal lobe epilepsy (TLE) and in the pentylenetetrazol (PTZ)-induced epileptic model. We demonstrate that GABA(A)R beta(2/3) and HAP1 expression are decreased and that the HAP1-GABA(A)R beta(2/3) complex is disrupted in the epileptic rat brain. We found that HAP1 upregulation exerts antiepileptic activity in the PTZ-induced seizure and that these changes are associated with increased surface GABA(A)R beta(2/3) expression and the amplitude of miniature inhibitory postsynaptic currents (mIPSCs). This study provides evidence that hippocampal HAP1 is linked to GABA(A)Rs in evoking seizures and suggests that this mechanism is involved in epileptic seizures in the brain, representing a potential therapeutic target for epilepsy.