HAP1 interacts with 14-3-3 to regulate epileptic seizure via GABA_AR-mediated inhibitory synaptic transmission in pentylenetetrazole rat model

Disruption of γ-aminobutyric acid type A receptors (GABA_ARs) synaptic clustering and a decrease number in the plasma membrane are thought to contribute to the alteration in the balance between excitatory and inhibitory neurotransmission in the epilepsy. Thus, it is important to elucidate the molecular mechanisms that regulate the stabilities of surface GABA_ARs populations as well as their concentrations at inhibitory synapses. However, the mechanism that delivers GABA_ARs to plasma membrane has not been conclusively determined. Our previous research indicated that huntingtin-associated protein 1 (HAP1), a major facilitator of pathological variations in membrane trafficking, modulates epileptic seizure by regulating GABA_ARs-mediated inhibitory synaptic transmission in pentylenetetrazole (PTZ)-induced epileptic rats. However, a detailed molecular interaction networks comprising GABA_ARs and HAP1 is necessary for studying and investigating new treatment targets for epilepsy. In this study, we indicate that HAP1 specifically interacts with 14-3-3, a protein that functions as a chaperone, forming a cargo adaptor complex to regulate surface GABA_ARs expression and the inhibitory post-synaptic current amplitudes. Disrupting the HAP1/14-3-3 complex decreases the strength of GABAARs-mediated inhibitory synaptic transmission in epilepsy. Taken together, HAP1/14-3-3 complex is linked to inhibitory synaptic transmission in evoking seizures, therefore, it is a possible drug target for epilepsy.