The number of γ-aminobutyric acid type A receptors (GABAARs) 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 GABAARs 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 GABAAR function in patients with temporal lobe epilepsy (TLE) and in the pentylenetetrazol (PTZ)-induced epileptic model. We demonstrate that GABAARβ2/3 and HAP1 expression are decreased and that the HAP1-GABAARβ2/3 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 GABAARβ2/3 expression and the amplitude of miniature inhibitory postsynaptic currents (mIPSCs). This study provides evidence that hippocampal HAP1 is linked to GABAARs in evoking seizures and suggests that this mechanism is involved in epileptic seizures in the brain, representing a potential therapeutic target for epilepsy.

中文翻译：

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HAP1通过调节颞叶癫痫患者和PTZ诱发的癫痫模型中的GABAAR功能来调节癫痫发作。

在表面膜上和突触部位表达的γ-氨基丁酸A型受体（GABAARs）的数量与癫痫中神经回路的兴奋性增强和异常的网络振荡有关。亨廷顿蛋白相关蛋白1（HAP1）是蛋白运输中病理变化的关键介体，它与GABAARs直接相互作用，并促进它们从表面内化后循环回突触；因此，HAP1调节抑制性突触传递的强度。在这里，我们显示HAP1通过调节颞叶癫痫（TLE）和戊四氮（PTZ）诱发的癫痫模型中的GABAAR功能来调节癫痫发作。我们证明，GABAARβ2/ 3和HAP1表达降低，并且HAP1-GABAARβ2/ 3复合物在癫痫大鼠脑中被破坏。我们发现，HAP1上调在PTZ诱发的癫痫发作中发挥抗癫痫活性，并且这些变化与表面GABAARβ2/ 3表达增加以及微型抑制性突触后电流（mIPSCs）的幅度有关。这项研究提供了证据，表明海马HAP1在诱发癫痫发作中与GABAARs相关，并表明该机制参与了大脑中的癫痫发作，代表了癫痫的潜在治疗靶标。